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RS62698B1 - Novel 6-6 bicyclic aromatic ring substituted nucleoside analogues for use as prmt5 inhibitors - Google Patents

Novel 6-6 bicyclic aromatic ring substituted nucleoside analogues for use as prmt5 inhibitors

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Publication number
RS62698B1
RS62698B1 RS20211526A RSP20211526A RS62698B1 RS 62698 B1 RS62698 B1 RS 62698B1 RS 20211526 A RS20211526 A RS 20211526A RS P20211526 A RSP20211526 A RS P20211526A RS 62698 B1 RS62698 B1 RS 62698B1
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Serbia
Prior art keywords
4alkyl
group
hydrogen
halo
represents hydrogen
Prior art date
Application number
RS20211526A
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Serbian (sr)
Inventor
Tongfei Wu
Dirk Brehmer
Lijs Beke
An Boeckx
Gaston Stanislas Marcella Diels
Ronaldus Arnodus Hendrika Joseph Gilissen
Edward Charles Lawson
Vineet Pande
Marcus Cornelis Bernardus Catharina Parade
Wim Bert Griet Schepens
Johannes Wilhelmus John F Thuring
Marcel Viellevoye
Weimei Sun
Lieven Meerpoel
Original Assignee
Janssen Pharmaceutica Nv
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
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Publication date
Application filed by Janssen Pharmaceutica Nv filed Critical Janssen Pharmaceutica Nv
Publication of RS62698B1 publication Critical patent/RS62698B1/en

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Description

Opis Description

Oblast pronalaska Field of invention

[0001] Predmetni pronalazak se odnosi na nove analoge nukleozida supstituisane 6-6 bicikličnim aromatičnim prstenom koji su korisni kao inhibitori PRMT5. Pronalazak se dalje odnosi na farmaceutske kompozicije koje sadrže navedena jedinjenja kao aktivni sastojak, kao i na upotrebu navedenih jedinjenja kao leka. [0001] The present invention relates to novel nucleoside analogs substituted with a 6-6 bicyclic aromatic ring that are useful as PRMT5 inhibitors. The invention further relates to pharmaceutical compositions containing said compounds as an active ingredient, as well as to the use of said compounds as medicine.

Osnova pronalaska Basis of the invention

[0002] PRMT5, koji se opisuje i kao Hsl7, Jbp1, Skb1, Capsuleen ili Dart5, jedan je od glavnih metiltransferaza koje su odgovorne za mono- i simetrično dimetilovanje arginina. Posttranslaciono metilovanje arginina na histonima i nehistonskim proteinima je verovatno ključno za različite biološke procese, kao što su organizacija genoma, transkripcija, diferencijacija, funkcija splajsozoma, transdukcija signala i regulisanje progresije ćelijskog ciklusa, sudbina matičnih ćelija i T-ćelija [Stopa, N. et al., Cell Mol Life Sci, 2015.72(11): str. [0002] PRMT5, also described as Hsl7, Jbp1, Skb1, Capsuleen or Dart5, is one of the main methyltransferases responsible for the mono- and symmetrical dimethylation of arginine. Post-translational methylation of arginine on histones and non-histone proteins is probably crucial for various biological processes, such as genome organization, transcription, differentiation, spliceosome function, signal transduction and regulation of cell cycle progression, stem cell and T-cell fate [Stopa, N. et al., Cell Mol Life Sci, 2015.72(11): p.

2041-59] [Geoghegan, V. et al., Nat Commun, 2015. 6: str. 6758]. PRMT5 višećelijskih životinja gradi funkcionalni kompleks sa metilozomskim proteinom 50 (MEP50), koji se naziva i Wdr77, koaktivatorom androgenog receptora p44 i Valois. I povišeni nivo proteina PRMT5-MEP50 i citoplazmatska akumulacija su umešani u tumorogenezu kancera, i nedavno su dovedeni u vezu sa lošim kliničkim ishodom [Shilo, K. et al., Diagn Pathol, 2013. 8: str. 2041-59] [Geoghegan, V. et al., Nat Commun, 2015. 6: p. 6758]. PRMT5 of multicellular animals forms a functional complex with methylosomal protein 50 (MEP50), also called Wdr77, a coactivator of the androgen receptor p44 and Valois. Both elevated PRMT5-MEP50 protein level and cytoplasmic accumulation have been implicated in cancer tumorigenesis, and have recently been linked to poor clinical outcome [Shilo, K. et al., Diagn Pathol, 2013. 8: p.

201]. Eksperimenti ćelijskog spasavanja koji su se bavili i katalitičkom funkcijom i funkcijom konstrukcije kompleksa PRMT5-MEP50, pored opsežnih enzimoloških studija su potvrdili onkogenu vezu između nivoa, lokalizacije i enzimske funkcije proteina [Gu, Z. et al., Biochem J, 2012.446(2): str. 235-41] [Di Lorenzo, A. et. al., FEBS Lett, 2011. 585(13): str.2024-31] [Chan-Penebre, E. et al., Nat Chem Biol, 2015.11(6): str.432-7]. Ova povezanost čini PRMT5 ključnim ciljnim lekom malog molekula, za kancer i druge bolesti [Stopa, N. et al., Cell Mol Life Sci, 2015.72(11): str.2041-59]. 201]. Cell rescue experiments dealing with both the catalytic function and the construction function of the PRMT5-MEP50 complex, in addition to extensive enzymological studies, confirmed the oncogenic link between the level, localization and enzymatic function of the protein [Gu, Z. et al., Biochem J, 2012.446(2): p. 235-41] [Di Lorenzo, A. et. al., FEBS Lett, 2011. 585(13): p.2024-31] [Chan-Penebre, E. et al., Nat Chem Biol, 2015.11(6): p.432-7]. This association makes PRMT5 a key small molecule drug target for cancer and other diseases [Stopa, N. et al., Cell Mol Life Sci, 2015.72(11): p.2041-59].

[0003] PRMT5 je član podfamilije PRMT tip II koji koristi S-adenozilmetionin (SAM) za stvaranje simetrično dimetilovanog arginina na histonima i nehistonskim proteinskim supstratima i S-adenozilhomocisteinu (SAH). Kristalna struktura humanog hetero-oktamernog kompleksa (PRMT5)4(MEP50)4kristalisanog zajedno sa SAH i histonskim H4 peptidnim supstratom ilustruje mehanizam metilovanja i prepoznavanja supstrata [Antonysamy, S. et al., Proc Natl Acad Sci U S A, 2012. 109(44): str. 17960-5]. Regulisanje aktivnosti PRMT5 se odvija putem mnogobrojnih različitih partnera za vezivanje, unakrsne komunikacije nakon translacione modifikacije, miRNK i subcelularne lokalizacije. [0003] PRMT5 is a member of the PRMT type II subfamily that uses S-adenosylmethionine (SAM) to generate symmetrically dimethylated arginine on histone and non-histone protein substrates and S-adenosylhomocysteine (SAH). Crystal structure of human hetero-octameric complex (PRMT5)4(MEP50)4 co-crystallized with SAH and histone H4 peptide substrate illustrates mechanism of methylation and substrate recognition [Antonysamy, S. et al., Proc Natl Acad Sci U S A, 2012. 109(44): p. 17960-5]. Regulation of PRMT5 activity occurs through multiple different binding partners, cross-talk after translational modification, miRNAs, and subcellular localization.

[0004] Metilovanje histona H2A i H4 na Arg3 i histona H3 na Arg8 reguliše organizaciju hromatina za specifično potiskivanje genskih transkripta koji učestvuju u diferencijaciji, transformaciji, progresiji ćelijskog ciklusa i supresiji tumora [Karkhanis, V. et al., Trends Biochem Sci, 2011. 36(12): str. 633-41]. Nadalje, PRMT5-posredovano metilovanje histona H4 na Arg3 moglo bi da regrutuje DNK-metiltransferazu DNMT3A za kupovanje histona i metilovanje DNK radi dugoročnog utišavanja gena [Zhao, Q. et al., Nat Struct Mol Biol, 2009. [0004] Methylation of histones H2A and H4 at Arg3 and histone H3 at Arg8 regulates chromatin organization for specific repression of gene transcripts involved in differentiation, transformation, cell cycle progression and tumor suppression [Karkhanis, V. et al., Trends Biochem Sci, 2011. 36(12): p. 633-41]. Furthermore, PRMT5-mediated methylation of histone H4 at Arg3 could recruit the DNA methyltransferase DNMT3A to purchase histones and methylate DNA for long-term gene silencing [Zhao, Q. et al., Nat Struct Mol Biol, 2009

16(3): str.304-11]. 16(3): pp.304-11].

[0005] Nehistonsko metilovanje može da se odigra ili u citoplazmi ili u jedru, u zavisnosti od ćelijske lokalizacije PRMT5. Metilovanje Sm proteina D1 i D3, koji su potrebni za sklapanje splajsozoma jedra, odvija se u citoplazmi u okviru PRMT5 koji sadrži „metilozom“ [Friesen, W.J. et al., Mol Cell Biol, 2001. 21(24): str.8289-300]. Dalji dokaz da je PRMT5 umešan u splajsovanje je obezbeđen putem uslovnog izbacivanja PRMT5 iz mišjih neuronskih matičnih ćelija. Ćelije koje nemaju PRMT5 pokazale su selektivnu retenciju introna i preskakanje egzona sa slabim 5' donorskim mestima [Bezzi, M. et al., Genes Dev, 2013.27(17): str.1903-16]. [0005] Non-histone methylation can take place either in the cytoplasm or in the nucleus, depending on the cellular localization of PRMT5. Methylation of the Sm proteins D1 and D3, which are required for core spliceosome assembly, occurs in the cytoplasm within the PRMT5 containing "methylosome" [Friesen, W.J. et al., Mol Cell Biol, 2001. 21(24): p.8289-300]. Further evidence that PRMT5 is involved in splicing was provided by conditionally knocking out PRMT5 from mouse neural stem cells. Cells lacking PRMT5 showed selective intron retention and exon skipping with weak 5' donor sites [Bezzi, M. et al., Genes Dev, 2013.27(17): p.1903-16].

[0006] Osim uloge u splajsovanju, PRMT5 utiče na ključne puteve koji učestvuju u ćelijskoj sudbini i homeostazi putem direktnog metilovanja ključnih signalnih nodula poput p53 [Jansson, M. et al., Nat Cell Biol, 2008.10(12): str.1431-9], EGFR [Hsu, J.M. et al., Nat Cell Biol, 2011.13(2): str. 174-81], CRAF [Andreu-Perez, P. et al., Sci Signal, 2011.4(190): str. [0006] In addition to its role in splicing, PRMT5 affects key pathways involved in cell fate and homeostasis through direct methylation of key signaling nodes such as p53 [Jansson, M. et al., Nat Cell Biol, 2008.10(12): p.1431-9], EGFR [Hsu, J.M. et al., Nat Cell Biol, 2011.13(2): p. 174-81], CRAF [Andreu-Perez, P. et al., Sci Signal, 2011.4(190): p.

ra58], PI3K/AKT [Wei, T.Y. et al., Cell Signal, 2014.26(12): str.2940-50], NFκB [Wei, H. et al., Proc Natl Acad Sci U S A, 2013.110(33): str.13516-21]. ra58], PI3K/AKT [Wei, T.Y. et al., Cell Signal, 2014.26(12): p.2940-50], NFκB [Wei, H. et al., Proc Natl Acad Sci U S A, 2013.110(33): p.13516-21].

[0007] Pošto je PRMT5 jedna od glavnih sym-Arg metiltransferaza i uključena je u više ćelijskih procesa, povećana proteinska ekspresija verovatno predstavlja značajan faktor u njegovoj tumorogenosti. Zanimljivo, izgleda da je translacija PRMT5 kod limfoma ćelija omotača (MCL) regulisana putem miRNK. Iako MCL ćelije pokazuju manje mRNK i sporiju transkripciju PRMT5 u odnosu na normalne B limfocite, nivo PRMT5 i metilovanje H3R8 i H4R3 su značajno povećani [Pal, S. et al., EMBO J, 2007. 26(15): str. 3558-69]. Ponovna ekspresija miRNK koje vezuju 3'UTR region PRMT5 smanjuje nivo proteina PRMT5 [Wang, L. et al., Mol Cell Biol, 2008. 28(20): str. 6262-77]. Iznenađujuće, antisens RNK prmt5 je otkrivena u humanom prmt5 genu, što podržava hipotezu o specifičnoj regulaciji translacije, a ne visok nivo ekspresije mRNK [Stopa, N. et al., Cell Mol Life Sci, 2015.72(11): str. 2041-59]. [0007] Since PRMT5 is one of the major sym-Arg methyltransferases and is involved in multiple cellular processes, increased protein expression is likely to be a significant factor in its tumorigenicity. Interestingly, translation of PRMT5 in mantle cell lymphoma (MCL) appears to be regulated via miRNA. Although MCL cells show less mRNA and slower transcription of PRMT5 compared to normal B lymphocytes, the level of PRMT5 and the methylation of H3R8 and H4R3 are significantly increased [Pal, S. et al., EMBO J, 2007. 26(15): p. 3558-69]. Re-expression of miRNAs that bind the 3'UTR region of PRMT5 reduces the protein level of PRMT5 [Wang, L. et al., Mol Cell Biol, 2008. 28(20): p. 6262-77]. Surprisingly, prmt5 antisense RNA was detected in the human prmt5 gene, supporting the hypothesis of specific translational regulation rather than high level mRNA expression [Stopa, N. et al., Cell Mol Life Sci, 2015.72(11): p. 2041-59].

[0008] Iako se PRMT5 smatra klinički relevantnim ciljem, za sada je objavljeno samo nekoliko selektivnih inhibitora PRMT5. Nedavno je novi subnanomolarni potentni inhibitor PRMT5 (EPZ015666) sa antitumorskom aktivnošću u više modela MCL ksenografta opisan kao prva hemijska sonda koja je pogodna za dalju potvrdu biologije i uloge PRMT5 kod kancera [Chan-Penebre, E. et al., Nat Chem Biol, 2015.11(6): str. 432-7]. [0008] Although PRMT5 is considered a clinically relevant target, only a few selective inhibitors of PRMT5 have been published so far. Recently, a novel subnanomolar potent inhibitor of PRMT5 (EPZ015666) with antitumor activity in multiple MCL xenograft models was described as the first chemical probe suitable for further confirmation of the biology and role of PRMT5 in cancer [Chan-Penebre, E. et al., Nat Chem Biol, 2015.11(6): p. 432-7].

[0009] Dalji razvoj specifičnih inhibitora malog molekula za PRMT5 može dovesti do novih hemoterapeutskih pristupa za kancer. [0009] Further development of specific small molecule inhibitors for PRMT5 may lead to new chemotherapeutic approaches for cancer.

[0010] WO2014100695A1 otkriva jedinjenja koja su korisna za inhibiciju aktivnosti PRMT5. Takođe su opisani postupci korišćenja jedinjenja za lečenje poremećaja koji su posredovani putem PRMT5. [0010] WO2014100695A1 discloses compounds useful for inhibiting PRMT5 activity. Also described are methods of using the compounds to treat disorders mediated by PRMT5.

[0011] WO2014100730A1 otkriva inhibitore PRMT5 koji sadrže dihidro- ili tetrahidroizohinolin i njihovu primenu. [0011] WO2014100730A1 discloses PRMT5 inhibitors containing dihydro- or tetrahydroisoquinoline and their use.

[0012] Devkota, K. et al., ACS Med Chem Lett, 2014. 5: p. 293-297, opisuju sintezu serije analoga prirodnog proizvoda sinefungina i sposobnost tih analoga da inhibiraju EHMT1 i EHMT2. [0012] Devkota, K. et al., ACS Med Chem Lett, 2014. 5: p. 293-297, describe the synthesis of a series of analogues of the natural product sinefungin and the ability of these analogues to inhibit EHMT1 and EHMT2.

[0013] WO2003070739 otkriva delimične i potpune agoniste adenozinskih receptora Al, njihovu pripremu, i njihovu terapeutsku primenu. [0013] WO2003070739 discloses partial and full agonists of adenosine receptors A1, their preparation, and their therapeutic use.

[0014] WO2012082436 otkriva jedinjenja i kompozicije kao modulatore histon metiltransferaza, i za lečenje bolesti na koje utiče modulacija aktivnosti histon metiltransferaze. [0014] WO2012082436 discloses compounds and compositions as modulators of histone methyltransferases, and for the treatment of diseases affected by modulation of histone methyltransferase activity.

[0015] WO2014100719 otkriva inhibitore PRMT5 i njihovu primenu. [0015] WO2014100719 discloses PRMT5 inhibitors and their use.

[0016] WO03074083 otkriva kombinovane terapije koje selektivno ubijaju ćelije sa deficitom metiltioadenozin fosforilaze. Analozi MTA su ovde opisani kao antitoksični agensi. [0016] WO03074083 discloses combination therapies that selectively kill cells deficient in methylthioadenosine phosphorylase. MTA analogs are described herein as antitoxic agents.

[0017] Kung, P.-P. et al., Bioorg Med Chem Lett, 2005. 15: str. 2829-2833, opisuju konstruisanje, sintezu i biološku procenu novih supstrata humane 5'-dezoksi-5'-metiltioadenozin fosforilaze (MTAP). [0017] Kung, P.-P. et al., Bioorg Med Chem Lett, 2005. 15: p. 2829-2833, describe the design, synthesis and biological evaluation of novel substrates of human 5'-deoxy-5'-methylthioadenosine phosphorylase (MTAP).

[0018] WO2012075500 otkriva 7-deazapurinske modulatore histon metiltransferaze. WO2014035140 otkriva jedinjenja i kompozicije za modulaciju aktivnosti histon metiltransferaze. [0018] WO2012075500 discloses 7-deazapurine modulators of histone methyltransferase. WO2014035140 discloses compounds and compositions for modulating histone methyltransferase activity.

[0019] WO2015200680 opisuje inhibitore PRMT5 i njihovu primenu. [0019] WO2015200680 describes PRMT5 inhibitors and their use.

[0020] Dakle postoji velika potreba za novim inhibitorima PRMT5, što otvara nove pravce za lečenje ili prevenciju kancera, kao što je, npr. limfom ćelija omotača. Prema tome, cilj predmetnog pronalaska je da obezbedi takva jedinjenja. [0020] Therefore, there is a great need for new inhibitors of PRMT5, which opens new directions for the treatment or prevention of cancer, such as, for example. mantle cell lymphoma. Therefore, it is an object of the present invention to provide such compounds.

[0021] Jedinjenja iz predmetnog pronalaska su strukturno različita i mogu imati poboljšana svojstva, kao što je, na primer, poboljšana potentnost ili poboljšana farmakokinetika (PK) i oralna bioraspoloživost, u poređenju sa jedinjenjima koja su otkrivena u prethodnom stanju tehnike. [0021] The compounds of the present invention are structurally different and may have improved properties, such as, for example, improved potency or improved pharmacokinetics (PK) and oral bioavailability, compared to compounds disclosed in the prior art.

Sažetak pronalaska Summary of the invention

[0022] Otkriveno je da su jedinjenja iz predmetnog pronalaska korisna kao inhibitori PRMT5. Jedinjenja prema pronalasku i njihove kompozicije stoga mogu biti korisni za lečenje ili prevenciju, naročito za lečenje, bolesti kao što su hematološki poremećaj, metabolički poremećaji, autoimunski poremećaji, kancer, inflamatorne bolesti, kardiovaskularne bolesti, neurodegenerativne bolesti, pankreatitis, zatajenje više organa, bolesti bubrega, agregacija trombocita, pokretljivost sperme, odbacivanje transplantata, odbacivanje grafta, povrede pluća, i slično. [0022] Compounds of the present invention have been found to be useful as PRMT5 inhibitors. The compounds according to the invention and their compositions can therefore be useful for the treatment or prevention, in particular for the treatment, of diseases such as hematological disorders, metabolic disorders, autoimmune disorders, cancer, inflammatory diseases, cardiovascular diseases, neurodegenerative diseases, pancreatitis, multiple organ failure, kidney diseases, platelet aggregation, sperm motility, graft rejection, graft rejection, lung injuries, and the like.

[0023] Predmetni pronalazak se bavi novim jedinjenjima formule (I): [0023] The present invention deals with new compounds of formula (I):

pri čemu whereby

R<1>predstavlja vodonik ili -C(=O)-C1-4alkil; R<1> represents hydrogen or -C(=O)-C1-4alkyl;

R<2>predstavlja vodonik ili -C(=O)-C1-4alkil; R<2> represents hydrogen or -C(=O)-C1-4alkyl;

Y predstavlja -CH2- ili -CF2-; Y represents -CH2- or -CF2-;

Z predstavlja -CH2-, -X-CR<5a>R<5b>-, -CR<5c>=CR<5d>-, -CR<5e>R<5g>-CR<5f>R<5h>-, -C≡C-, -O-, ili -CR<5a>R<5b>-X-; Z represents -CH2-, -X-CR<5a>R<5b>-, -CR<5c>=CR<5d>-, -CR<5e>R<5g>-CR<5f>R<5h>-, -C≡C-, -O-, or -CR<5a>R<5b>-X-;

R<5a>, R<5b>, R<5c>, R<5d>, R<5e>, R<5f>, R<5g>i R<5h>svaki nezavisno predstavlja vodonik ili C1-4alkil; R<5a>, R<5b>, R<5c>, R<5d>, R<5e>, R<5f>, R<5g> and R<5h> each independently represents hydrogen or C1-4alkyl;

X predstavlja -O-, -S-, ili -NR<11>-; X represents -O-, -S-, or -NR<11>-;

R<11>predstavlja vodonik, C1-4alkil, ili C1-4alkil supstituisan jednim supstituentom izabranim iz grupe koju čine -OH, -O-C1-4alkil, R<12>, -NH2, -NH-C1-4alkil i -N(C1-4alkil)2; R<12>predstavlja 4-, 5-, 6- ili 7-člani heterociklični prsten koji sadrži jedan atom azota i opciono jedan atom kiseonika, pri čemu je navedeni 4-, 5-, 6- ili 7-člani heterociklični prsten povezan sa ostatkom molekula preko atoma azota prstena; R<11> represents hydrogen, C1-4alkyl, or C1-4alkyl substituted with one substituent selected from the group consisting of -OH, -O-C1-4alkyl, R<12>, -NH2, -NH-C1-4alkyl and -N(C1-4alkyl)2; R<12>represents a 4-, 5-, 6- or 7-membered heterocyclic ring containing one nitrogen atom and optionally one oxygen atom, wherein said 4-, 5-, 6- or 7-membered heterocyclic ring is connected to the rest of the molecule via a nitrogen atom of the ring;

[0024] Ar predstavlja 10-člani biciklični aromatični sistem prstenova koji se sastoji od dva kondenzovana 6-člana prstena, [0024] Ar represents a 10-membered bicyclic aromatic ring system consisting of two fused 6-membered rings,

pri čemu je najmanje 1 atom ugljenika prstena B zamenjen atomom azota; wherein at least 1 carbon atom of ring B is replaced by a nitrogen atom;

pri čemu je opciono 1 dodatni atom ugljenika prstena A ili prstena B zamenjen atomom azota, pod uslovom da, kada atom azota zamenjuje jedan od dva kondenzovana atoma ugljenika, karbonilna grupa je prisutna u navedenom bicikličnom aromatičnom sistemu prstenova; wherein optionally 1 additional carbon atom of ring A or ring B is replaced by a nitrogen atom, provided that, when the nitrogen atom replaces one of the two fused carbon atoms, a carbonyl group is present in said bicyclic aromatic ring system;

Ar je opciono supstituisan sa jednim, dva, tri ili četiri supstituenta od kojih je svaki nezavisno izabran iz grupe koju čine halo, -OH, -NH2, -NH-C1-4alkil, -N(C1-4alkil)2, -NHR<10d>, -NR<10c>R<10d>, cijano, -CF3, -C(=O)-NH2, -C(=O)-NH-C1-4alkil, -C(=O)-C1-4alkil, C1-4alkiloksi, -C(=O)-O-C1-4alkil, C3-6cikloalkil, -O-C3-6cikloalkil, -NH-C3-6cikloalkil, -N(C3-6cikloalkil)2, C2-6alkenil, C1-4alkil supstituisan jednim C1-4alkiloksi i C1-4alkil opciono supstituisan jednim -NR<10a>R<10b>; R<10a>i R<10b>svaki nezavisno predstavlja vodonik ili C1-4alkil; Ar is optionally substituted with one, two, three or four substituents each independently selected from the group consisting of halo, -OH, -NH2, -NH-C1-4alkyl, -N(C1-4alkyl)2, -NHR<10d>, -NR<10c>R<10d>, cyano, -CF3, -C(=O)-NH2, -C(=O)-NH-C1-4alkyl, -C(=O)-C1-4alkyl, C1-4alkyloxy, -C(=O)-O-C1-4alkyl, C3-6cycloalkyl, -O-C3-6cycloalkyl, -NH-C3-6cycloalkyl, -N(C3-6cycloalkyl)2, C2-6alkenyl, C1-4alkyl substituted with one C1-4alkyloxy and C1-4alkyl optionally substituted with one -NR<10a>R<10b>; R<10a> and R<10b> each independently represents hydrogen or C1-4alkyl;

R<10c>i R<10d>svaki nezavisno predstavlja C3-6cikloalkil; R<13>; R<14>; C3-6cikloalkil supstituisan sa jednim, dva ili tri supstituenta od kojih je svaki nezavisno izabran iz grupe koju čine halo, -OH i -O-C1-4alkil; C1-4alkil supstituisan sa jednim, dva ili tri supstituenta od kojih je svaki nezavisno izabran iz grupe koju čine halo, -OH i -O-C1-R<10c> and R<10d> each independently represents C3-6cycloalkyl; R<13>; R<14>; C3-6cycloalkyl substituted with one, two or three substituents each independently selected from the group consisting of halo, -OH and -O-C1-4alkyl; C1-4alkyl substituted with one, two or three substituents each independently selected from the group consisting of halo, -OH and -O-C1-

4alkil; ili C1-4alkil supstituisan jednim supstituentom izabranim iz grupe koju čine C3-4alkyl; or C1-4alkyl substituted with one substituent selected from the group consisting of C3-

6cikloalkil, R<13>i R<14>; 6cycloalkyl, R<13> and R<14>;

R<13>predstavlja 4- do 7-člani monociklični aromatični prsten koji sadrži jedan, dva ili tri heteroatoma, svaki nezavisno izabran od O, S, S(=O)pi N; ili 6- do 11-člani biciklični kondenzovani aromatični prsten koji sadrži jedan, dva ili tri heteroatoma, svaki nezavisno izabran od O, S, S(=O)pi N; R<13>represents a 4- to 7-membered monocyclic aromatic ring containing one, two or three heteroatoms, each independently selected from O, S, S(=O) and N; or a 6- to 11-membered bicyclic fused aromatic ring containing one, two or three heteroatoms, each independently selected from O, S, S(=O) and N;

navedeni 4- do 7-člani monociklični aromatični prsten ili 6- do 11-člani biciklični kondenzovani aromatični prsten je opciono supstituisan sa jednim ili dva supstituenta izabrana iz grupe koju čini C1-4alkil; said 4- to 7-membered monocyclic aromatic ring or 6- to 11-membered bicyclic fused aromatic ring is optionally substituted with one or two substituents selected from the group consisting of C1-4alkyl;

p predstavlja 1 ili 2; p represents 1 or 2;

R<14>predstavlja fenil opciono supstituisan sa jednim, dva ili tri supstituenta od kojih je svaki nezavisno izabran iz grupe koju čini halo; R<14>represents phenyl optionally substituted with one, two or three substituents each independently selected from the group consisting of halo;

Het predstavlja biciklični aromatični heterociklični sistem prstenova izabran iz grupe koju čine (a-1), (a-2), (a-3), (a-4) i (a-5): Het represents a bicyclic aromatic heterocyclic ring system selected from the group consisting of (a-1), (a-2), (a-3), (a-4) and (a-5):

R<3a>, R<3b>, R<3c>, R<3d>i R<3e>svaki nezavisno predstavlja vodonik, halo, -NR<7a>R<7b>, C1-4alkil, C2-4alkenil, C3-6cikloalkil, -OH ili -O-C1-4alkil; R<3a>, R<3b>, R<3c>, R<3d>and R<3e> each independently represents hydrogen, halo, -NR<7a>R<7b>, C1-4alkyl, C2-4alkenyl, C3-6cycloalkyl, -OH or -O-C1-4alkyl;

R<7a>predstavlja vodonik; R<7a> represents hydrogen;

R<7b>predstavlja vodonik, C3-6cikloalkil, ili C1-4alkil; R<7b>represents hydrogen, C3-6cycloalkyl, or C1-4alkyl;

R<4a>, R<4b>, R<4c>, R<4d>, R<4e>, R<4f>i R<4g>svaki nezavisno predstavlja vodonik, halo, -NR<8a>R<8b>, ili C1-4alkil; R<4a>, R<4b>, R<4c>, R<4d>, R<4e>, R<4f> and R<4g> each independently represents hydrogen, halo, -NR<8a>R<8b>, or C1-4alkyl;

R<8a>i R<8b>svaki nezavisno predstavlja vodonik ili C1-4alkil; R<8a> and R<8b> each independently represents hydrogen or C1-4alkyl;

Q<1>predstavlja N ili CR<6a>; Q<1>represents N or CR<6a>;

Q<2>predstavlja N ili CR<6b>; Q<2>represents N or CR<6b>;

Q<3>predstavlja N ili CR<6c>; Q<3>represents N or CR<6c>;

Q<4>predstavlja N ili CR<6d>; Q<4>represents N or CR<6d>;

pod uslovom da najviše jedan od Q<3>i Q<4>predstavlja N; provided that at most one of Q<3> and Q<4> represents N;

Q<8>predstavlja N ili CR<6g>; Q<8> represents N or CR<6g>;

Q<9>predstavlja N ili CR<6h>; Q<9> represents N or CR<6h>;

Q<10>predstavlja N ili CR<6i>; Q<10>represents N or CR<6i>;

Q<11>predstavlja N ili CR<6j>; Q<11> represents N or CR<6j>;

Q<5>predstavlja CR<3d>; Q<6>predstavlja N; i Q<7>predstavlja CR<4f>; ili Q<5> represents CR<3d>; Q<6>represents N; and Q<7>represents CR<4f>; or

Q<5>predstavlja CR<3d>; Q<6>predstavlja CR<4e>; i Q<7>predstavlja N; ili Q<5> represents CR<3d>; Q<6>represents CR<4e>; and Q<7>represents N; or

Q<5>predstavlja N; Q<6>predstavlja CR<4e>; i Q<7>predstavlja CR<4f>; ili Q<5>represents N; Q<6>represents CR<4e>; and Q<7>represents CR<4f>; or

Q<5>predstavlja N; Q<6>predstavlja CR<4e>; i Q<7>predstavlja N; ili Q<5>represents N; Q<6>represents CR<4e>; and Q<7>represents N; or

Q<5>predstavlja N; Q<6>predstavlja N; i Q<7>predstavlja CR<4f>; ili Q<5>represents N; Q<6>represents N; and Q<7>represents CR<4f>; or

Q<5>predstavlja N; Q<6>predstavlja N; i Q<7>predstavlja N; Q<5>represents N; Q<6>represents N; and Q<7>represents N;

R<6a>, R<6b>, R<6c>, R<6d>, R<6e>, R<6f>, R<6g>, R<6h>, R<6i>i R<6j>svaki nezavisno predstavlja vodonik, halogen, C1-4alkil, -NR<9a>R<9b>, ili C1-4alkil supstituisan sa jednim, dva ili tri halo atoma; R<6a>, R<6b>, R<6c>, R<6d>, R<6e>, R<6f>, R<6g>, R<6h>, R<6i> and R<6j> each independently represents hydrogen, halogen, C1-4alkyl, -NR<9a>R<9b>, or C1-4alkyl substituted with one, two or three halo atoms;

R<9a>i R<9b>svaki nezavisno predstavlja vodonik ili C1-4alkil; R<9a> and R<9b> each independently represents hydrogen or C1-4alkyl;

i njegovim farmaceutski prihvatljivim adicionim solima i solvatima. and pharmaceutically acceptable addition salts and solvates thereof.

[0025] Predmetni pronalazak se takođe odnosi na postupke za pripremu jedinjenja iz predmetnog pronalaska i farmaceutskih kompozicija koje ih sadrže. [0025] The present invention also relates to methods for the preparation of the compounds of the present invention and pharmaceutical compositions containing them.

[0026] Otkriveno je da jedinjenja iz predmetnog pronalaska inhibiraju PRMT5 sama po sebi, ili mogu biti metabolisana u aktivan (aktivniji) oblik in vivo (prolekovi), te stoga mogu biti korisna u lečenju ili prevenciji, naročito u lečenju, bolesti kao što su hematološki poremećaj, metabolički poremećaji, autoimunski poremećaji, kancer, inflamatorne bolesti, kardiovaskularne bolesti, neurodegenerativne bolesti, pankreatitis, zatajenje više organa, bolesti bubrega, agregacija trombocita, pokretljivost sperme, odbacivanje transplantata, odbacivanje grafta, povrede pluća, i slično. [0026] It has been discovered that the compounds of the present invention inhibit PRMT5 by themselves, or can be metabolized to an active (more active) form in vivo (prodrugs), and therefore can be useful in the treatment or prevention, especially in the treatment, of diseases such as hematological disorders, metabolic disorders, autoimmune disorders, cancer, inflammatory diseases, cardiovascular diseases, neurodegenerative diseases, pancreatitis, multiple organ failure, kidney diseases, platelet aggregation, sperm motility, transplant rejection, graft rejection, lung injury, and the like.

[0027] Imajući u vidu prethodno pomenutu farmakologiju jedinjenja formule (I) i njihovih farmaceutski prihvatljivih adicionih soli i solvata, zaključuje se da ona mogu biti korisna za upotrebu u vidu leka. [0027] Having in mind the previously mentioned pharmacology of compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates, it is concluded that they can be useful for use in the form of medicine.

[0028] Jedinjenja formule (I) i njihove farmaceutski prihvatljive adicione soli i solvati naročito mogu biti korisni u lečenju ili prevenciji, naročito u lečenju, bilo koje bolesti ili stanja koji su ovde navedeni prethodno ili u nastavku, naročito kancera. [0028] The compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates may be particularly useful in the treatment or prevention, particularly in the treatment, of any of the diseases or conditions listed hereinabove or below, particularly cancer.

[0029] Predmetni pronalazak se takođe odnosi na upotrebu jedinjenja formule (I), i njihovih farmaceutski prihvatljivih adicionih soli i solvata, za proizvodnju leka za inhibiciju PRMT5, za lečenje ili prevenciju bilo koje bolesti ili stanja koji su ovde navedeni prethodno ili u nastavku, naročito kancera. [0029] The present invention also relates to the use of compounds of formula (I), and their pharmaceutically acceptable addition salts and solvates, for the manufacture of a medicament for inhibiting PRMT5, for the treatment or prevention of any disease or condition hereinbefore or below, particularly cancer.

[0030] Predmetni pronalazak će sada biti detaljnije opisan. U sledećim pasusima, različiti aspekti pronalaska su detaljnije definisani. Svaki aspekt koji je tako definisan može da se [0030] The subject invention will now be described in more detail. In the following paragraphs, various aspects of the invention are defined in more detail. Each aspect that is defined in this way can be

1 1

kombinuje sa bilo kojim drugim aspektom ili aspektima, osim ako nije jasno naznačeno drugačije. Naročito, svako svojstvo koje je označeno kao poželjno ili povoljno može da se kombinuje sa bilo kojim drugim svojstvom ili svojstvima koja su označena kao poželjna ili povoljna. combined with any other aspect or aspects, unless clearly indicated otherwise. In particular, any property designated as desirable or advantageous may be combined with any other property or properties designated as desirable or advantageous.

Detaljan opis Detailed description

[0031] Prilikom opisivanja jedinjenja iz pronalaska, termine koji se koriste treba tumačiti u skladu sa sledećim definicijama, osim ako kontekst ne nalaže drugačije. [0031] When describing the compounds of the invention, the terms used should be interpreted in accordance with the following definitions, unless the context dictates otherwise.

[0032] Kada se bilo koja promenljiva javi više od jednom u bilo kom konstituentu ili u bilo kojoj formuli (npr. formuli (I)), njena definicija za svaku pojavljivanje je nezavisna od njene definicije za svako drugo pojavljivanje. [0032] When any variable occurs more than once in any constituent or in any formula (eg formula (I)), its definition for each occurrence is independent of its definition for every other occurrence.

[0033] Svaki put kada se termin „supstituisano“ koristi u predmetnom pronalasku, ako nije drugačije naznačeno ili jasno iz konteksta, on treba da znači da je jedan ili više vodonika, naročito od 1 do 3 vodonika, poželjno 1 ili 2 vodonika, poželjnije 1 vodonik, na atomu ili radikalu koji je označen u frazi koja koristi „supstituisano“ zamenjen odabirom iz naznačene grupe, pod uslovom da uobičajena valenca nije premašena i da supstitucija dovodi do hemijski stabilnog jedinjenja, tj. jedinjenja koje je dovoljno robusno da preživi izolovanje iz reakcione smeše do korisnog stepena čistoće, i formulisanje u terapeutski agens. [0033] Whenever the term "substituted" is used in the present invention, unless otherwise indicated or clear from the context, it shall mean that one or more hydrogens, especially from 1 to 3 hydrogens, preferably 1 or 2 hydrogens, more preferably 1 hydrogen, on the atom or radical indicated in the phrase using "substituted" is replaced by one selected from the indicated group, provided that the usual valence is not exceeded and that the substitution results to a chemically stable compound, i.e. compounds that are robust enough to survive isolation from the reaction mixture to a useful degree of purity, and formulation into a therapeutic agent.

[0034] Kada je dva ili više supstituenata prisutno u ostatku, ako nije drugačije naznačeno ili jasno iz konteksta, oni mogu da zamene vodonike na istom atomu, ili mogu da zamene atome vodonika na različitim atomima u ostatku. [0034] When two or more substituents are present in a residue, unless otherwise indicated or clear from the context, they may replace hydrogens on the same atom, or may replace hydrogen atoms on different atoms in the residue.

[0035] Prefiks (gde su x i y celi brojevi), kako se ovde koristi, odnosi se na broj atoma ugljenika u datoj grupi. Tako, C1-4alkil grupa sadrži od 1 do 4 atoma ugljenika, C1-3alkil grupa sadrži 1 do 3 atoma ugljenika, i tako dalje. [0035] The prefix (where x and y are integers), as used herein, refers to the number of carbon atoms in a given group. Thus, a C 1-4 alkyl group contains from 1 to 4 carbon atoms, a C 1-3 alkyl group contains 1 to 3 carbon atoms, and so on.

[0036] Termin „halo“ kao grupa ili deo grupe je uopšten termin za fluor, hlor, brom, jod, osim ako nije drugačije naznačeno ili jasno iz konteksta. [0036] The term "halo" as a group or part of a group is a general term for fluorine, chlorine, bromine, iodine, unless otherwise indicated or clear from the context.

[0037] Termin kao grupa ili deo grupe odnosi se na hidrokarbil radikal formule CnH2n+1, pri čemu je n broj u rasponu od 1 do 4. C1-4alkil grupe sadrže od 1 do 4 atoma ugljenika, poželjno od 1 do 3 atoma ugljenika, poželjnije 1 do 2 atoma ugljenika. C1-4alkil grupa može biti ravna ili razgranata, i može biti supstituisana kako je ovde naznačeno. Kada se indeks ovde koristi nakon atoma ugljenika, indeks se odnosi na broj atoma ugljenika koje navedena grupa može da sadrži. C1-4alkil uključuje sve linearne ili razgranate alkil grupe sa od 1 do 4 atoma ugljenika, te tako uključuje metil, etil, n-propil, i-propil, 2-metil-etil, butil i njegove izomere (npr. n-butil, izobutil i terc-butil), i slično. [0037] The term group or part of a group refers to a hydrocarbyl radical of the formula CnH2n+1, where n is a number in the range of 1 to 4. C1-4alkyl groups contain from 1 to 4 carbon atoms, preferably from 1 to 3 carbon atoms, more preferably from 1 to 2 carbon atoms. The C 1-4 alkyl group may be straight or branched, and may be substituted as indicated herein. When a subscript is used herein after a carbon atom, the subscript refers to the number of carbon atoms that said group may contain. C1-4alkyl includes all linear or branched alkyl groups having from 1 to 4 carbon atoms, and thus includes methyl, ethyl, n-propyl, i-propyl, 2-methyl-ethyl, butyl and isomers thereof (eg, n-butyl, isobutyl and tert-butyl), and the like.

[0038] Stručnjaku će biti jasno da termin „C1-4alkoksi“ ili „C1-4alkiloksi“ kao grupa ili deo grupe označava radikal sa formulom -OR<c>, pri čemu, R<c>je C1-4alkil. Neograničavajući primeri za pogodni C1-4alkiloksi uključuju metiloksi (takođe metoksi), etiloksi (takođe etoksi), propiloksi, izopropiloksi, butiloksi, izobutiloksi, sek-butiloksi i terc-butiloksi. [0038] It will be clear to the person skilled in the art that the term "C1-4alkyloxy" or "C1-4alkyloxy" as a group or part of a group means a radical of the formula -OR<c>, wherein, R<c>is C1-4alkyl. Non-limiting examples of suitable C 1-4 alkyloxy include methyloxy (also methoxy), ethyloxy (also ethoxy), propyloxy, isopropyloxy, butyloxy, isobutyloxy, sec-butyloxy and tert-butyloxy.

[0039] Termin kako se ovde koristi, kao grupa ili deo grupe, predstavlja ugljovodoničnu grupu sa ravnim ili razgranatim nizom koja sadrži od 2 do 4 atoma ugljenika i sadrži dvostruku vezu ugljenik ugljenik, kao što je, bez ograničenja, etenil, propenil, butenil, 1-propen-2-il, i slično. [0039] The term as used herein, as a group or part of a group, represents a straight or branched chain hydrocarbon group containing from 2 to 4 carbon atoms and containing a carbon carbon double bond, such as, without limitation, ethenyl, propenyl, butenyl, 1-propen-2-yl, and the like.

[0040] Termin kako se ovde koristi, kao grupa ili deo grupe, predstavlja ugljovodoničnu grupu sa ravnim ili razgranatim nizom koja sadrži od 2 do 6 atoma ugljenika i sadrži dvostruku vezu ugljenik ugljenik, kao što je, bez ograničenja, etenil, propenil, butenil, pentenil, 1-propen-2-il, heksenil, i slično. [0040] The term as used herein, as a group or part of a group, represents a straight or branched chain hydrocarbon group containing from 2 to 6 carbon atoms and containing a carbon carbon double bond, such as, without limitation, ethenyl, propenyl, butenyl, pentenyl, 1-propen-2-yl, hexenyl, and the like.

[0041] Termin kako se ovde koristi, kao grupa ili deo grupe, predstavlja ciklične zasićene ugljovodonične radikale koji imaju od 3 do 6 atoma ugljenika, kao što je ciklopropil, ciklobutil, ciklopentil ili cikloheksil. [0041] The term as used herein, as a group or part of a group, represents cyclic saturated hydrocarbon radicals having from 3 to 6 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

[0042] U slučaju da je Z -X-CR<5a>R<5b>-, predviđeno je da je X vezan za Ar. [0042] In case Z is -X-CR<5a>R<5b>-, it is provided that X is attached to Ar.

[0043] U slučaju da Z predstavlja -CR<5c>=CR<5d>-, predviđeno je da je C atom sa supstituentom R<5c>vezan za Ar. [0043] In the event that Z represents -CR<5c>=CR<5d>-, it is foreseen that the C atom with the substituent R<5c> is attached to Ar.

[0044] U slučaju da Z predstavlja -CR<5e>R<5g>-CR<5f>R<5h>-, predviđeno je da je atom C sa supstituentima R<5e>i R<5g>vezan za Ar. [0044] In case Z represents -CR<5e>R<5g>-CR<5f>R<5h>-, it is foreseen that the C atom with the substituents R<5e>and R<5g> is attached to Ar.

[0045] U slučaju da Z predstavlja -CR<5a>R<5b>-X-, predviđeno je da je atom C sa supstituentima R<5a>i R<5b>vezan za Ar. [0045] In the event that Z represents -CR<5a>R<5b>-X-, it is foreseen that the atom C with the substituents R<5a> and R<5b> is bound to Ar.

[0046] Stručnjaku je jasno da će 4-, 5-, 6- ili 7-člani heterociklični prsten koji je vezan sa ostatkom molekula preko atoma azota prstena (u definiciji za R<12>) konkretno biti zasićeni prsten. Neograničavajući primeri R<12>su 1-piperidinil, 1-pirolidinil, 1-morfolinil, 1-azetidinil, i slično. [0046] It is clear to a person skilled in the art that a 4-, 5-, 6- or 7-membered heterocyclic ring that is linked to the rest of the molecule via a ring nitrogen atom (in the definition for R<12>) will specifically be a saturated ring. Non-limiting examples of R<12> are 1-piperidinyl, 1-pyrrolidinyl, 1-morpholinyl, 1-azetidinyl, and the like.

[0047] Stručnjaku će biti jasno da, osim ako nije drugačije naznačeno ili jasno iz konteksta, supstituent na 4- do 7-članom monocikličnom aromatičnom prstenu koji sadrži jedan, dva ili tri heteroatoma (kao u definiciji za R<13>) (neograničavajući primeri su pirolil, piridinil, furanil, i slično), može da zameni bilo koji atom vodonika na atomu ugljenika prstena ili, gde je to moguće, na atomu azota prstena (u tom slučaju vodonik na atomu azota može biti zamenjen supstituentom). Stručnjaku će biti jasno da isto važi za 6- do 11-člani biciklični kondenzovani aromatični prsten koji sadrži jedan, dva ili tri heteroatoma (kao u definiciji za R<13>) (neograničavajući primeri su indolil, hinolinil, i slično). [0047] It will be clear to one skilled in the art that, unless otherwise indicated or clear from the context, a substituent on a 4- to 7-membered monocyclic aromatic ring containing one, two, or three heteroatoms (as in the definition for R<13>) (non-limiting examples are pyrrolyl, pyridinyl, furanyl, and the like), may replace any hydrogen atom on a ring carbon atom or, where possible, on a nitrogen atom. ring (in this case the hydrogen on the nitrogen atom can be replaced by a substituent). One skilled in the art will appreciate that the same is true for a 6- to 11-membered bicyclic fused aromatic ring containing one, two, or three heteroatoms (as in the definition for R<13>) (non-limiting examples are indolyl, quinolinyl, and the like).

[0048] 4- do 7-člani monociklični aromatični prsten koji sadrži jedan, dva ili tri heteroatoma (kao u definiciji za R<13>), može po potrebi biti povezan sa ostatkom molekula formule (I) preko bilo kog dostupnog atoma ugljenika ili azota u prstenu, ako nije drugačije naznačeno. Stručnjaku će biti jasno da isto važi za 6- do 11-člani biciklični kondenzovani aromatični prsten koji sadrži jedan, dva ili tri heteroatoma (kao u definiciji za R<13>). [0048] A 4- to 7-membered monocyclic aromatic ring containing one, two or three heteroatoms (as in the definition for R<13>), may optionally be linked to the rest of the molecule of formula (I) via any available carbon or nitrogen atom in the ring, unless otherwise indicated. One skilled in the art will appreciate that the same is true for a 6- to 11-membered bicyclic fused aromatic ring containing one, two, or three heteroatoms (as in the definition for R<13>).

[0049] U slučaju da atom azota zamenjuje jedan od dva kondenzovana atoma ugljenika u Ar grupi, karbonil grupa je prisutna u navedenom bicikličnom aromatičnom sistemu prstenova, kako je prikazano strukturom u nastavku: [0049] In the event that a nitrogen atom replaces one of the two condensed carbon atoms in the Ar group, a carbonyl group is present in the aforementioned bicyclic aromatic ring system, as shown by the structure below:

1 1

koja je opciono supstituisana prema bilo kom od otelotvorenja. Biće jasno da je ovaj primer neograničavajući. which is optionally substituted according to any of the embodiments. It will be understood that this example is non-limiting.

[0050] Drugi, neograničavajući primeri Ar grupe koja je 10-člani biciklični aromatični sistem prstenova koji se sastoji od dva fuzionisana 6-člana prstena, pri čemu je opciono 1 ili 2 atoma ugljenika zamenjeno atomom azota, prikazani su u nastavku: [0050] Other, non-limiting examples of an Ar group which is a 10-membered bicyclic aromatic ring system consisting of two fused 6-membered rings, optionally with 1 or 2 carbon atoms replaced by a nitrogen atom, are shown below:

od kojih je svaki opciono supstituisan prema bilo kom od otelotvorenja. each of which is optionally substituted according to any of the embodiments.

[0051] Stručnjaku će biti jasno da je 10 članova 10-člane Ar grupe (10-člani biciklični aromatični sistem prstenova koji se sastoji od dva kondenzovana 6-člana prstena, pri čemu je opciono 1 ili 2 atoma ugljenika prstena zamenjeno atomom azota) 10 atoma ugljenika, 9 atoma ugljenika i 1 atom azota, ili 8 atoma ugljenika i 2 atoma azota. Ar je opciono supstituisan prema bilo kom od otelotvorenja. [0051] It will be clear to a person skilled in the art that 10 members of a 10-membered Ar group (a 10-membered bicyclic aromatic ring system consisting of two fused 6-membered rings, with optionally 1 or 2 ring carbon atoms replaced by a nitrogen atom) are 10 carbon atoms, 9 carbon atoms and 1 nitrogen atom, or 8 carbon atoms and 2 nitrogen atoms. Ar is optionally substituted according to any of the embodiments.

[0052] Svaki put kada su supstituenti predstavljeni hemijskom strukturom, „---“ predstavlja vezu za povezivanje sa ostatkom molekula formule (I). Linije povučene od supstituenata do sistema prstenova pokazuju da veza može biti vezana za bilo koji od odgovarajućih atoma prstena. [0052] Whenever substituents are represented by a chemical structure, "---" represents a bond to connect to the rest of the molecule of formula (I). Lines drawn from the substituents to the ring system show that the bond can be attached to any of the corresponding ring atoms.

[0053] Na primer [0053] For example

obuhvata bilo koji od sledećih sistema prstenova: includes any of the following ring systems:

je alternativni prikaz za is an alternative representation for

[0054] Termin „ispitanik“, kako se ovde koristi, odnosi se na životinju, poželjno sisara (npr. mačka, pas, primat ili čovek), poželjnije čoveka, koja jeste, ili je bila, predmet lečenja, posmatranja ili eksperimenta. [0054] The term "subject", as used herein, refers to an animal, preferably a mammal (eg, cat, dog, primate or human), more preferably a human, that is, or has been, the subject of treatment, observation or experimentation.

[0055] Termin „terapeutski delotvorna količina“, kako se ovde koristi, označava onu količinu aktivnog jedinjenja ili farmaceutskog agensa koja izaziva biološki ili medicinski odgovor u sistemu tkiva, životinji ili čoveku, koji traže istraživač, veterinar, lekar ili klinički lekar, što obuhvata ublažavanje ili uklanjanje simptoma bolesti ili poremećaja koji se leči. [0055] The term "therapeutically effective amount," as used herein, means that amount of an active compound or pharmaceutical agent that elicits a biological or medical response in a tissue system, animal, or human being sought by the investigator, veterinarian, physician, or clinical practitioner, which includes alleviation or elimination of symptoms of the disease or disorder being treated.

[0056] Termin „kompozicija“ treba da obuhvata proizvod koji sadrži naznačene sastojke u naznačenim količinama, kao i bilo koji proizvod koji se dobija, neposredno ili posredno, od kombinacije naznačenih sastojaka u naznačenim količinama. [0056] The term "composition" should include a product containing the indicated ingredients in the indicated amounts, as well as any product obtained, directly or indirectly, from a combination of the indicated ingredients in the indicated amounts.

1 1

[0057] Termin „lečenje“, kako se ovde koristi, treba da se odnosi na sve procese kod kojih može doći do usporavanja, prekidanja, zaustavljanja ili stopiranja progresije bolesti, ali ne mora nužno da ukazuje na potpuno otklanjanje svih simptoma. [0057] The term "treatment", as used herein, should refer to all processes in which the progression of the disease can be slowed down, interrupted, stopped or halted, but does not necessarily indicate the complete elimination of all symptoms.

[0058] Termin „jedinjenja iz (predmetnog) pronalaska“, kako se ovde koristi, treba da obuhvata jedinjenja formule (I) i njihove farmaceutski prihvatljive adicione soli i solvate. [0058] The term "compounds of the (subject) invention", as used herein, should include compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates.

[0059] Neka od jedinjenja formule (I) mogu takođe postojati u svojim tautomernim oblicima. Termin „tautomer“ ili „tautomerni oblik“ odnosi se na strukturne izomere različite energije koji mogu da se konvertuju iz jednog u drugi putem niskoenergetske barijere. Na primer, protonski tautomeri (poznati i kao prototropni tautomeri) uključuju međusobnu konverziju putem migracije protona, kao što su keto-enolna i imin-enaminska izomerizacija. Valentni tautomeri uključuju međusobnu konverziju putem reorganizacije nekih od vezujućih elektrona. [0059] Some of the compounds of formula (I) may also exist in their tautomeric forms. The term "tautomer" or "tautomeric form" refers to structural isomers of different energy that can be converted from one to the other via a low-energy barrier. For example, proton tautomers (also known as prototropic tautomers) involve interconversion via proton migration, such as keto-enol and imine-enamine isomerization. Valence tautomers involve interconversion via reorganization of some of the bonding electrons.

[0060] Predviđeno je da takvi oblici, u meri u kojoj postoje, iako nisu izričito naznačeni u prethodnoj formuli (I), budu obuhvaćeni opsegom predmetnog pronalaska. [0060] It is envisaged that such forms, to the extent that they exist, although not explicitly indicated in the preceding formula (I), are covered by the scope of the present invention.

[0061] Kako se ovde koristi, svaka hemijska formula u kojoj su veze prikazane samo kao pune linije, a ne kao pune klinaste ili isprekidane klinaste veze, ili je na drugi način naznačeno da ima određenu konfiguraciju (npr. R, S) oko jednog ili više atoma, razmatra svaki mogući stereoizomer ili smešu dva ili više stereoizomera. Kada stereohemija bilo kog konkretnog hiralnog atoma nije naznačena u ovde prikazanim strukturama, svi stereoizomeri su razmatrani i uključeni kao jedinjenja iz pronalaska, bilo kao čisti stereoizomer ili kao smeša dva ili više stereoizomera. [0061] As used herein, any chemical formula in which bonds are shown as solid lines only and not as solid wedge or dashed wedge bonds, or otherwise indicated as having a particular configuration (eg, R, S) about one or more atoms, contemplates every possible stereoisomer or mixture of two or more stereoisomers. When the stereochemistry of any particular chiral atom is not indicated in the structures shown herein, all stereoisomers are contemplated and included as compounds of the invention, either as a pure stereoisomer or as a mixture of two or more stereoisomers.

[0062] U prethodnom delu i u nastavku ovog teksta, termin „jedinjenje formule (I)“ treba da uključuje njegove stereoizomere i njegove tautomerne oblike. Međutim, kada je stereohemija, kako je navedeno u prethodnom paragrafu, naznačena putem veza koje su prikazane kao pune klinaste ili isprekidane klinaste veze, ili je na drugi način naznačeno da ima određenu konfiguraciju (npr. R, S), stereoizomer je onda time naznačen i definisan. Biće jasno da se to takođe odnosi na podgrupe formule (I). [0062] In the foregoing and in the remainder of this text, the term "compound of formula (I)" shall include its stereoisomers and its tautomeric forms. However, when stereochemistry, as noted in the preceding paragraph, is indicated by bonds shown as full wedge or broken wedge bonds, or is otherwise indicated to have a particular configuration (eg, R, S), the stereoisomer is then indicated and defined thereby. It will be clear that this also applies to subgroups of formula (I).

[0063] Odatle sledi da pojedinačno jedinjenje može, gde je to moguće, da postoji i u stereoizomernom i u tautomernom obliku. [0063] It follows that an individual compound can, where possible, exist in both stereoisomeric and tautomeric forms.

1 1

[0064] Termini „stereoizomeri“, „stereoizomerni oblici“ ili „stereohemijski izomerni oblici“ u prethodnom delu i u nastavku ovog teksta koriste se naizmenično. [0064] The terms "stereoisomers", "stereoisomeric forms" or "stereochemically isomeric forms" in the previous section and in the rest of this text are used interchangeably.

[0065] Enantiomeri su stereoizomeri koji su međusobni nepreklapajući odrazi u ogledalu. 1: 1 smeša para enantiomera je racemat ili racemska smeša. [0065] Enantiomers are stereoisomers that are non-overlapping mirror images of each other. A 1:1 mixture of a pair of enantiomers is a racemate or racemic mixture.

[0066] Atropizomeri (ili atropoizomeri) su stereoizomeri koji imaju posebnu prostornu konfiguraciju, usled ograničene rotacije oko jedne veze, usled velike sterne smetnje. Svi atropizomerni oblici jedinjenja formule (I) treba da budu obuhvaćeni opsegom predmetnog pronalaska. [0066] Atropisomers (or atropoisomers) are stereoisomers that have a special spatial configuration, due to limited rotation around one bond, due to large steric hindrance. All atropisomeric forms of the compounds of formula (I) are intended to be included within the scope of the present invention.

[0067] Dijastereomeri (ili dijastereoizomeri) su stereoizomeri koji nisu enantiomeri, tj. nisu povezani kao odrazi u ogledalu. Ako jedinjenje sadrži dvostruku vezu, supstituenti mogu imati E ili Z konfiguraciju. Supstituenti na dvovalentnim cikličnim (delimično) zasićenim radikalima mogu imati cis- ili trans-konfiguraciju. Na primer, ako jedinjenje sadrži disupstituisanu cikloalkil grupu, supstituenti mogu imati cis ili trans konfiguraciju. Stoga, pronalazak obuhvata enantiomere, atropizomere, dijastereomere, racemate, E izomere, Z izomere, cis izomere, trans izomere i njihove smeše, kad god je to hemijski moguće. [0067] Diastereomers (or diastereoisomers) are stereoisomers that are not enantiomers, ie. they are not related like mirror images. If the compound contains a double bond, the substituents may have an E or Z configuration. Substituents on divalent cyclic (partially) saturated radicals can have cis- or trans-configuration. For example, if the compound contains a disubstituted cycloalkyl group, the substituents may have a cis or trans configuration. Therefore, the invention includes enantiomers, atropisomers, diastereomers, racemates, E isomers, Z isomers, cis isomers, trans isomers and mixtures thereof, whenever chemically possible.

[0068] Značenje svih ovih termina, tj. enantiomeri, atropizomeri, dijastereomeri, racemati, E izomeri, Z izomeri, cis izomeri, trans izomeri i njihove smeše, poznato je stručnjaku. [0068] The meaning of all these terms, ie. enantiomers, atropisomers, diastereomers, racemates, E isomers, Z isomers, cis isomers, trans isomers and mixtures thereof, are known to the expert.

[0069] Apsolutna konfiguracija je naznačena prema Kan-Ingold-Prelogovom sistemu. Konfiguracija na asimetričnom atomu je naznačena sa R ili S. Razdvojeni stereoizomeri čija apsolutna konfiguracija nije poznata mogu biti označeni sa (+) ili (-) u zavisnosti od smera u kome obrću ravan polarizovane svetlosti. Na primer, razdvojeni enantiomeri čija apsolutna konfiguracija nije poznata mogu biti označeni sa (+) ili (-) u zavisnosti od smera u kom obrću ravan polarizovane svetlosti. [0069] The absolute configuration is indicated according to the Kahn-Ingold-Prelog system. The configuration on the asymmetric atom is indicated by R or S. Separated stereoisomers whose absolute configuration is not known can be marked (+) or (-) depending on the direction in which they rotate the plane of polarized light. For example, separated enantiomers whose absolute configuration is not known may be labeled (+) or (-) depending on the direction in which the plane of polarized light rotates.

[0070] Kada je identifikovan specifični stereoizomer, to znači da je navedeni stereoizomer suštinski bez drugih stereoizomera, tj. povezan je sa manje od 50%, poželjno manje od 20%, poželjnije manje od 10%, još poželjnije manje od 5%, naročito manje od 2%, a najpoželjnije manje od 1%, drugih stereoizomera. Tako, kada je jedinjenje formule (I), na primer, označeno [0070] When a specific stereoisomer is identified, it means that said stereoisomer is essentially free of other stereoisomers, ie. is associated with less than 50%, preferably less than 20%, more preferably less than 10%, more preferably less than 5%, especially less than 2%, and most preferably less than 1%, of other stereoisomers. Thus, when a compound of formula (I), for example, is labeled

1 1

kao (R), to znači da je jedinjenje suštinski bez (S) izomera. Kada je jedinjenje formule (I), na primer, označeno kao E, to znači da je jedinjenje suštinski bez Z izomera. Kada je jedinjenje formule (I), na primer, označeno kao cis, to znači da je jedinjenje suštinski bez trans izomera. as (R), it means that the compound is essentially free of (S) isomers. When a compound of formula (I), for example, is designated as E, this means that the compound is essentially free of the Z isomer. When a compound of formula (I), for example, is designated as cis, this means that the compound is essentially free of the trans isomer.

[0071] Soli jedinjenja formule (I) i njihovi solvati za farmaceutsku upotrebu su oni u kojima je kontrajon farmaceutski prihvatljiv. Međutim, soli kiselina i baza koje nisu farmaceutski prihvatljive takođe mogu naći primenu, na primer, u pripremi ili prečišćavanju farmaceutski prihvatljivog jedinjenja. Sve soli, bilo da su farmaceutski prihvatljive ili ne, uključene su u obim predmetnog pronalaska. [0071] Salts of compounds of formula (I) and solvates thereof for pharmaceutical use are those in which the counterion is pharmaceutically acceptable. However, salts of acids and bases which are not pharmaceutically acceptable may also find use, for example, in the preparation or purification of a pharmaceutically acceptable compound. All salts, whether pharmaceutically acceptable or not, are included within the scope of the present invention.

[0072] Farmaceutski prihvatljive soli uključuju kisele adicione soli i bazne adicione soli. Takve soli mogu da se formiraju uobičajenim putem, na primer, reakcijom oblika slobodne kiseline ili slobodne baze sa jednim ili više ekvivalenata odgovarajuće kiseline ili baze, opciono u rastvaraču, ili u medijumu u kome je so nerastvorljiva, nakon čega sledi uklanjanje navedenog rastvarača, ili navedenog medijuma, koristeći standardne tehnike (npr. pod vakuumom, liofilizacijom ili filtracijom). Soli takođe mogu da se pripreme razmenom kontrajona jedinjenja iz pronalaska u obliku soli drugim kontrajonom, na primer, koristeći odgovarajuću jonoizmenjivačku smolu. [0072] Pharmaceutically acceptable salts include acid addition salts and base addition salts. Such salts can be formed by conventional means, for example, by reacting the free acid or free base form with one or more equivalents of the corresponding acid or base, optionally in a solvent, or in a medium in which the salt is insoluble, followed by removal of said solvent, or said medium, using standard techniques (eg, under vacuum, lyophilization, or filtration). Salts can also be prepared by exchanging the counterion of a salt compound of the invention with another counterion, for example, using a suitable ion exchange resin.

[0073] Farmaceutski prihvatljive adicione soli, kako se pominju prethodno ili u nastavku ovog teksta, treba da obuhvataju oblike terapeutski aktivnih netoksičnih kiselih i baznih adicionih soli koje jedinjenja formule (I) i njihovi solvati mogu da grade. [0073] Pharmaceutically acceptable addition salts, as mentioned above or below, should include the forms of therapeutically active non-toxic acid and base addition salts that the compounds of formula (I) and their solvates can form.

[0074] Odgovarajuće kiseline sadrže, na primer, neorganske kiseline kao što su halovodonične kiseline, npr. hlorovodonična ili bromovodonična kiselina, sumporna, azotna, fosforna i slične kiseline, ili organske kiseline kao što su, na primer, sirćetna, propanska, hidroksi sirćetna, mlečna, piruvinska, oksalna (tj. etandionska), malonska, sukcinska (tj. butandionska kiselina), maleinska, fumarna, jabučna, vinska, limunska, metansulfonska, etansulfonska, benzensulfonska, p-toluensulfonska, ciklaminska, salicilna, p-aminosalicilna, pamoinska, i slične kiseline. Nasuprot tome, navedeni oblici soli tretiranjem odgovarajućom bazom mogu da se konvertuju u oblik slobodne baze. [0074] Suitable acids include, for example, inorganic acids such as hydrochloric acids, e.g. hydrochloric or hydrobromic acid, sulfuric, nitric, phosphoric and similar acids, or organic acids such as, for example, acetic, propanoic, hydroxyacetic, lactic, pyruvic, oxalic (i.e. ethanedione), malonic, succinic (i.e. butanedione acid), maleic, fumaric, malic, tartaric, citric, methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic, cyclamic, salicylic, p-aminosalicylic, pamoic, and similar acids. Conversely, the above salt forms can be converted to the free base form by treatment with an appropriate base.

1 1

[0075] Jedinjenja formule (I) i njihovi solvati koji sadrže kiseli proton takođe mogu da se konvertuju u svoje oblike adicione soli netoksičnog metala ili amina tretiranjem odgovarajućim organskim i neorganskim bazama. [0075] Compounds of formula (I) and their acidic proton-containing solvates can also be converted to their non-toxic metal or amine addition salt forms by treatment with appropriate organic and inorganic bases.

[0076] Odgovarajući oblici baznih soli obuhvataju, na primer, soli amonijaka, soli alkalnih i zemnoalkalnih metala, npr. soli litijuma, natrijuma, kalijuma, magnezijuma, kalcijuma, i slično, soli sa organskim bazama, npr. primarnim, sekundarnim i tercijarnim alifatičnim i aromatičnim aminima, kao što su metilamin, etilamin, propilamin, izopropilamin, četiri izomera butilamina, dimetilamin, dietilamin, dietanolamin, dipropilamin, diizopropilamin, di-n-butilamin, pirolidin, piperidin, morfolin, trimetilamin, trietilamin, tripropilamin, hinuklidin, piridin, hinolin i izohinolin; benzatin, N-metil-D-glukamin, soli hidrabamina i soli sa aminokiselinama, kao što su, na primer, arginin, lizin, i slično. Nasuprot tome, oblik soli može da se konvertuje tretiranjem kiselinom u oblik slobodne kiseline. [0076] Suitable base salt forms include, for example, ammonia salts, alkali and alkaline earth metal salts, e.g. salts of lithium, sodium, potassium, magnesium, calcium, and the like, salts with organic bases, e.g. primary, secondary and tertiary aliphatic and aromatic amines, such as methylamine, ethylamine, propylamine, isopropylamine, four isomers of butylamine, dimethylamine, diethylamine, diethanolamine, dipropylamine, diisopropylamine, di-n-butylamine, pyrrolidine, piperidine, morpholine, trimethylamine, triethylamine, tripropylamine, quinuclidine, pyridine, quinoline and isoquinoline; benzathine, N-methyl-D-glucamine, hydrabamine salts and salts with amino acids, such as, for example, arginine, lysine, and the like. Conversely, the salt form can be converted by acid treatment to the free acid form.

[0077] Kako bi se izbegla sumnja, termin „parenteralna“ primena obuhvata sve oblike primene osim oralne primene, naročito intravensku (i.v.), intramuskularnu (i.m.) i supkutanu (s.c.) injekciju. [0077] For the avoidance of doubt, the term "parenteral" administration includes all forms of administration other than oral administration, particularly intravenous (i.v.), intramuscular (i.m.) and subcutaneous (s.c.) injection.

[0078] Termin solvat obuhvata hidrate i adicione oblike rastvarača koje jedinjenja formule (I) mogu da grade, kao i njihove farmaceutski prihvatljive adicione soli. Primeri za takve oblike su, npr. hidrati, alkoholati, i slično. The term solvate includes hydrates and solvent addition forms that compounds of formula (I) can form, as well as their pharmaceutically acceptable addition salts. Examples of such forms are, e.g. hydrates, alcoholates, and the like.

[0079] Jedinjenja iz pronalaska pripremana u procesima koji su opisani u nastavku mogu da se sintetišu u obliku smeša enantiomera, naročito racemskih smeša enantiomera, koje mogu međusobno da se razdvoje prateći procedure razdvajanja poznate u struci. Postupak razdvajanja enantiomernih oblika jedinjenja formule (I) i njihovih farmaceutski prihvatljivih adicionih soli od njihovih solvata uključuje tečnu hromatografiju koristeći hiralnu stacionarnu fazu. Navedeni stereohemijski čisti izomerni oblici takođe mogu da se dobiju od odgovarajućih stereohemijski čistih izomernih oblika odgovarajućih polaznih supstanci, pod uslovom da se reakcija odvija stereospecifično. Poželjno, ako se želi specifičan stereoizomer, navedeno jedinjenje bi se sintetisalo stereospecifičnim postupcima pripreme. Ovi postupci će pogodno koristiti enantiomerno čiste polazne supstance. [0079] The compounds of the invention prepared in the processes described below can be synthesized in the form of mixtures of enantiomers, especially racemic mixtures of enantiomers, which can be separated from each other following separation procedures known in the art. A process for separating enantiomeric forms of compounds of formula (I) and their pharmaceutically acceptable addition salts from their solvates involves liquid chromatography using a chiral stationary phase. Said stereochemically pure isomeric forms can also be obtained from the corresponding stereochemically pure isomeric forms of the corresponding starting substances, provided that the reaction proceeds stereospecifically. Preferably, if a specific stereoisomer is desired, said compound would be synthesized by stereospecific preparation procedures. These processes will conveniently use enantiomerically pure starting substances.

1 1

[0080] Predmetni pronalazak takođe obuhvata izotopski obeležena jedinjenja iz predmetnog pronalaska koja su identična onima koja su ovde navedena, osim činjenice da je jedan ili više atoma zamenjeno atomom koji ima atomsku masu ili maseni broj različite od atomske mase ili masenog broja koji se obično može naći u prirodi (ili koji se pretežno može naći u prirodi). [0080] The present invention also includes isotopically labeled compounds of the present invention that are identical to those listed herein, except that one or more atoms have been replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number commonly found in nature (or predominantly found in nature).

[0081] Svi izotopi i izotopske smeše bilo kog konkretnog atoma ili elementa koji su ovde naznačeni razmatraju se u opsegu jedinjenja iz pronalaska, bilo da su prirodni ili sintetički proizvedeni, bilo u prirodnoj zastupljenosti ili u izotopski obogaćenom obliku. Primeri izotopa koji mogu biti uključeni u jedinjenja iz pronalaska uključuju izotope vodonika, ugljenika, azota, kiseonika, fosfora, sumpora, fluora, hlora i joda, kao što su<2>H,<3>H,<11>C,<13>C,<14>C ,<13>N,<15>O,<17>O,<18>O,<32>P,<33>P,<35>S,<18>F,<36>Cl<122>I,<123>I,<125>I,<131>I,<75>Br,<76>Br,<77>Br i<82>Br. Radioaktivni izotop je poželjno izabran iz grupe<2>H,<3>H,<11>C i<18>F. Poželjnije, radioaktivni izotop je<2>H. Deuterisana jedinjenja naročito treba da budu obuhvaćena opsegom predmetnog pronalaska. [0081] All isotopes and isotopic mixtures of any particular atom or element indicated herein are contemplated within the scope of the compounds of the invention, whether naturally occurring or synthetically produced, whether naturally occurring or in isotopically enriched form. Examples of isotopes that may be included in the compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine, such as<2>H,<3>H,<11>C,<13>C,<14>C ,<13>N,<15>O,<17>O,<18>O,<32>P,<33>P,<35>S,<18>F,<36>Cl<122>I,<123>I,<125>I,<131>I,<75>Br,<76>Br,<77>Br and<82>Br. The radioactive isotope is preferably selected from the group<2>H,<3>H,<11>C and<18>F. More preferably, the radioactive isotope is <2>H. Deuterated compounds are particularly intended to be included within the scope of the present invention.

[0082] Određena izotopski obeležena jedinjenja iz predmetnog pronalaska (npr. ona obeležena sa<3>H i<14>C) korisna su u jedinjenju i za testove distribucije supstrata u tkivu. Tricijumski (<3>H) i ugljenik-14 (<14>C) izotopi su korisni zbog svoje lakoće pripreme i mogućnosti detekcije. Nadalje, supstitucija težim izotopima kao što je deuterijum (tj.<2>H) može da obezbedi određene terapeutske koristi usled veće metaboličke stabilnosti (npr. produženi poluživot in vivo ili smanjeni dozni zahtevi), te stoga može biti poželjno u nekim okolnostima. Izotopi koji emituju pozitrone, kao što su<15>O,<13>N,<11>C i<18>F, korisni su za preglede pozitronskom emisionom tomografijom (PET) za ispitivanje zauzetosti receptora supstrata. [0082] Certain isotopically labeled compounds of the present invention (eg, those labeled with<3>H and<14>C) are useful in compound and tissue distribution assays of substrates. Tritium (<3>H) and carbon-14 (<14>C) isotopes are useful because of their ease of preparation and detection capabilities. Furthermore, substitution with heavier isotopes such as deuterium (ie, <2>H) may provide certain therapeutic benefits due to greater metabolic stability (eg, prolonged in vivo half-life or reduced dosage requirements), and thus may be desirable in some circumstances. Positron-emitting isotopes, such as<15>O,<13>N,<11>C and<18>F, are useful for positron emission tomography (PET) scans to probe substrate receptor occupancy.

[0083] U jednom otelotvorenju, predmetni pronalazak se bavi novim jedinjenjima formule (I), pri čemu [0083] In one embodiment, the present invention relates to novel compounds of formula (I), wherein

R<1>predstavlja vodonik ili -C(=O)-C1-4alkil; R<1> represents hydrogen or -C(=O)-C1-4alkyl;

R<2>predstavlja vodonik ili -C(=O)-C1-4alkil; R<2> represents hydrogen or -C(=O)-C1-4alkyl;

Y predstavlja -CH2- ili -CF2-; Y represents -CH2- or -CF2-;

Z predstavlja -CH2-, -X-CR<5a>R<5b>-, -CR<5c>=CR<5d>-, -CR<5e>R<5g>-CR<5f>R<5h>-, -C≡C-, -O-, ili -CR<5a>R<5b>-X-; Z represents -CH2-, -X-CR<5a>R<5b>-, -CR<5c>=CR<5d>-, -CR<5e>R<5g>-CR<5f>R<5h>-, -C≡C-, -O-, or -CR<5a>R<5b>-X-;

2 2

R<5a>, R<5b>, R<5c>, R<5d>, R<5e>, R<5f>, R<5g>i R<5h>svaki nezavisno predstavlja vodonik ili C1-4alkil; R<5a>, R<5b>, R<5c>, R<5d>, R<5e>, R<5f>, R<5g> and R<5h> each independently represents hydrogen or C1-4alkyl;

X predstavlja -O-, -S-, ili -NR<11>-; X represents -O-, -S-, or -NR<11>-;

R<11>predstavlja vodonik ili C1-4alkil; R<11> represents hydrogen or C1-4alkyl;

Ar predstavlja 10-člani biciklični aromatični sistem prstenova koji se sastoji od dva kondenzovana 6-člana prstena, Ar represents a 10-membered bicyclic aromatic ring system consisting of two fused 6-membered rings,

pri čemu je najmanje 1 atom ugljenika prstena B zamenjen atomom azota; wherein at least 1 carbon atom of ring B is replaced by a nitrogen atom;

pri čemu je opciono 1 dodatni atom ugljenika prstena A ili prstena B zamenjen atomom azota, pod uslovom da, kada atom azota zamenjuje jedan od dva kondenzovana atoma ugljenika, karbonilna grupa je prisutna u navedenom bicikličnom aromatičnom sistemu prstenova; wherein optionally 1 additional carbon atom of ring A or ring B is replaced by a nitrogen atom, provided that, when the nitrogen atom replaces one of the two fused carbon atoms, a carbonyl group is present in said bicyclic aromatic ring system;

Ar je opciono supstituisan sa jednim, dva, tri ili četiri supstituenta od kojih je svaki nezavisno izabran iz grupe koju čine halo, -OH, -NH2, -NH-C1-4alkil, -N(C1-4alkil)2, -NHR<10d>, -NR<10c>R<10d>, cijano, -CF3, -C(=O)-NH2, -C(=O)-NH-C1-4alkil, -C(=O)-C1-4alkil, C1-4alkiloksi, -C(=O)-O-C1-4alkil, C3-6cikloalkil, -O-C3-6cikloalkil, -NH-C3-6cikloalkil, -N(C3-6cikloalkil)2, C2-6alkenil, C1-4alkil supstituisan jednim C1-4alkiloksi i C1-4alkil opciono supstituisan jednim -NR<10a>R<10b>; Ar is optionally substituted with one, two, three or four substituents each independently selected from the group consisting of halo, -OH, -NH2, -NH-C1-4alkyl, -N(C1-4alkyl)2, -NHR<10d>, -NR<10c>R<10d>, cyano, -CF3, -C(=O)-NH2, -C(=O)-NH-C1-4alkyl, -C(=O)-C1-4alkyl, C1-4alkyloxy, -C(=O)-O-C1-4alkyl, C3-6cycloalkyl, -O-C3-6cycloalkyl, -NH-C3-6cycloalkyl, -N(C3-6cycloalkyl)2, C2-6alkenyl, C1-4alkyl substituted with one C1-4alkyloxy and C1-4alkyl optionally substituted with one -NR<10a>R<10b>;

R<10a>i R<10b>svaki nezavisno predstavlja vodonik ili C1-4alkil; R<10a> and R<10b> each independently represents hydrogen or C1-4alkyl;

R<10c>i R<10d>svaki nezavisno predstavlja C3-6cikloalkil; R<14>; C3-6cikloalkil supstituisan sa jednim, dva ili tri supstituenta od kojih je svaki nezavisno izabran iz grupe koju čine halo, -OH i -O-C1-4alkil; C1-4alkil supstituisan sa jednim, dva ili tri supstituenta od kojih je svaki nezavisno izabran iz grupe koju čine halo, -OH i -O-C1-4alkil; ili C1-4alkil supstituisan jednim supstituentom izabranim iz grupe koju čine C3-6cikloalkil i R<14>; R<10c> and R<10d> each independently represents C3-6cycloalkyl; R<14>; C3-6cycloalkyl substituted with one, two or three substituents each independently selected from the group consisting of halo, -OH and -O-C1-4alkyl; C1-4alkyl substituted with one, two or three substituents each independently selected from the group consisting of halo, -OH and -O-C1-4alkyl; or C1-4alkyl substituted with one substituent selected from the group consisting of C3-6cycloalkyl and R<14>;

R<14>predstavlja fenil opciono supstituisan sa jednim, dva ili tri supstituenta od kojih je svaki nezavisno izabran iz grupe koju čini halo; R<14>represents phenyl optionally substituted with one, two or three substituents each independently selected from the group consisting of halo;

Het predstavlja biciklični aromatični heterociklični sistem prstenova izabran iz grupe koju čine (a-1), (a-2), (a-3), (a-4) i (a-5): Het represents a bicyclic aromatic heterocyclic ring system selected from the group consisting of (a-1), (a-2), (a-3), (a-4) and (a-5):

R<3a>, R<3b>, R<3c>, R<3d>i R<3e>svaki nezavisno predstavlja vodonik, halo, -NR<7a>R<7b>, C1-4alkil, C2-4alkenil, C3-6cikloalkil, -OH ili -O-C1-4alkil; R<3a>, R<3b>, R<3c>, R<3d>and R<3e> each independently represents hydrogen, halo, -NR<7a>R<7b>, C1-4alkyl, C2-4alkenyl, C3-6cycloalkyl, -OH or -O-C1-4alkyl;

R<7a>predstavlja vodonik; R<7a> represents hydrogen;

R<7b>predstavlja vodonik, C3-6cikloalkil, ili C1-4alkil; R<7b>represents hydrogen, C3-6cycloalkyl, or C1-4alkyl;

R<4a>, R<4b>, R<4c>, R<4d>, R<4e>, R<4f>i R<4g>svaki nezavisno predstavlja vodonik, halo, -NR<8a>R<8b>, ili C1-4alkil; R<4a>, R<4b>, R<4c>, R<4d>, R<4e>, R<4f> and R<4g> each independently represents hydrogen, halo, -NR<8a>R<8b>, or C1-4alkyl;

R<8a>i R<8b>svaki nezavisno predstavlja vodonik ili C1-4alkil; R<8a> and R<8b> each independently represents hydrogen or C1-4alkyl;

Q<1>predstavlja N ili CR<6a>; Q<1>represents N or CR<6a>;

Q<2>predstavlja N ili CR<6b>; Q<2>represents N or CR<6b>;

Q<3>predstavlja N ili CR<6c>; Q<3>represents N or CR<6c>;

Q<4>predstavlja N ili CR<6d>; Q<4>represents N or CR<6d>;

pod uslovom da najviše jedan od Q<3>i Q<4>predstavlja N; provided that at most one of Q<3> and Q<4> represents N;

Q<8>predstavlja N ili CR<6g>; Q<8> represents N or CR<6g>;

Q<9>predstavlja N ili CR<6h>; Q<9> represents N or CR<6h>;

Q<10>predstavlja N ili CR<6i>; Q<10>represents N or CR<6i>;

Q<11>predstavlja N ili CR<6j>; Q<11> represents N or CR<6j>;

Q<5>predstavlja CR<3d>; Q<6>predstavlja N; i Q<7>predstavlja CR<4f>; ili Q<5> represents CR<3d>; Q<6>represents N; and Q<7>represents CR<4f>; or

Q<5>predstavlja CR<3d>; Q<6>predstavlja CR<4e>; i Q<7>predstavlja N; ili Q<5> represents CR<3d>; Q<6>represents CR<4e>; and Q<7>represents N; or

Q<5>predstavlja N; Q<6>predstavlja CR<4e>; i Q<7>predstavlja CR<4f>; ili Q<5>represents N; Q<6>represents CR<4e>; and Q<7>represents CR<4f>; or

Q<5>predstavlja N; Q<6>predstavlja CR<4e>; i Q<7>predstavlja N; ili Q<5>represents N; Q<6>represents CR<4e>; and Q<7>represents N; or

Q<5>predstavlja N; Q<6>predstavlja N; i Q<7>predstavlja CR<4f>; ili Q<5>represents N; Q<6>represents N; and Q<7>represents CR<4f>; or

Q<5>predstavlja N; Q<6>predstavlja N; i Q<7>predstavlja N; Q<5>represents N; Q<6>represents N; and Q<7>represents N;

R<6a>, R<6b>, R<6c>, R<6d>, R<6e>, R<6f>, R<6g>, R<6h>, R<6i>i R<6j>svaki nezavisno predstavlja vodonik, halogen, C1-4alkil, -NR<9a>R<9b>, ili C1-4alkil supstituisan sa jednim, dva ili tri halo atoma; R<6a>, R<6b>, R<6c>, R<6d>, R<6e>, R<6f>, R<6g>, R<6h>, R<6i> and R<6j> each independently represents hydrogen, halogen, C1-4alkyl, -NR<9a>R<9b>, or C1-4alkyl substituted with one, two or three halo atoms;

R<9a>i R<9b>svaki nezavisno predstavlja vodonik ili C1-4alkil; R<9a> and R<9b> each independently represents hydrogen or C1-4alkyl;

i njegovim farmaceutski prihvatljivim adicionim solima i solvatima. and pharmaceutically acceptable addition salts and solvates thereof.

2 2

[0084] U jednom otelotvorenju, predmetni pronalazak se bavi novim jedinjenjima formule (I), pri čemu [0084] In one embodiment, the present invention relates to novel compounds of formula (I), wherein

R<1>predstavlja vodonik ili -C(=O)-C1-4alkil; R<1> represents hydrogen or -C(=O)-C1-4alkyl;

R<2>predstavlja vodonik ili -C(=O)-C1-4alkil; R<2> represents hydrogen or -C(=O)-C1-4alkyl;

Y predstavlja -CH2- ili -CF2-; Y represents -CH2- or -CF2-;

Z predstavlja -CH2-, -X-CR<5a>R<5b>-, -CR<5c>=CR<5d>-, -CR<5e>R<5g>-CR<5f>R<5h>-, -C≡C-, -O-, ili -CR<5a>R<5b>-X-; Z represents -CH2-, -X-CR<5a>R<5b>-, -CR<5c>=CR<5d>-, -CR<5e>R<5g>-CR<5f>R<5h>-, -C≡C-, -O-, or -CR<5a>R<5b>-X-;

R<5a>, R<5b>, R<5c>, R<5d>, R<5e>, R<5f>, R<5g>i R<5h>svaki nezavisno predstavlja vodonik ili C1-4alkil; R<5a>, R<5b>, R<5c>, R<5d>, R<5e>, R<5f>, R<5g> and R<5h> each independently represents hydrogen or C1-4alkyl;

X predstavlja -O-, -S-, ili -NR<11>-; X represents -O-, -S-, or -NR<11>-;

R<11>predstavlja vodonik, C1-4alkil, ili C1-4alkil supstituisan jednim supstituentom izabranim iz grupe koju čine -OH, -O-C1-4alkil, R<12>, -NH2, -NH-C1-4alkil i -N(C1-4alkil)2; R<11> represents hydrogen, C1-4alkyl, or C1-4alkyl substituted with one substituent selected from the group consisting of -OH, -O-C1-4alkyl, R<12>, -NH2, -NH-C1-4alkyl and -N(C1-4alkyl)2;

R<12>predstavlja 4-, 5-, 6- ili 7-člani heterociklični prsten koji sadrži jedan atom azota i opciono jedan atom kiseonika, pri čemu je navedeni 4-, 5-, 6- ili 7-člani heterociklični prsten povezan sa ostatkom molekula preko atoma azota prstena; R<12>represents a 4-, 5-, 6- or 7-membered heterocyclic ring containing one nitrogen atom and optionally one oxygen atom, wherein said 4-, 5-, 6- or 7-membered heterocyclic ring is connected to the rest of the molecule via a nitrogen atom of the ring;

Ar predstavlja 10-člani biciklični aromatični sistem prstenova koji se sastoji od dva kondenzovana 6-člana prstena, Ar represents a 10-membered bicyclic aromatic ring system consisting of two fused 6-membered rings,

pri čemu je najmanje 1 atom ugljenika prstena B zamenjen atomom azota; wherein at least 1 carbon atom of ring B is replaced by a nitrogen atom;

pri čemu je opciono 1 dodatni atom ugljenika prstena A ili prstena B zamenjen atomom azota, pod uslovom da, kada atom azota zamenjuje jedan od dva kondenzovana atoma ugljenika, karbonilna grupa je prisutna u navedenom bicikličnom aromatičnom sistemu prstenova; wherein optionally 1 additional carbon atom of ring A or ring B is replaced by a nitrogen atom, provided that, when the nitrogen atom replaces one of the two fused carbon atoms, a carbonyl group is present in said bicyclic aromatic ring system;

Ar je opciono supstituisan sa jednim, dva, tri ili četiri supstituenta od kojih je svaki nezavisno izabran iz grupe koju čine halo, -OH, -NH2, -NH-C1-4alkil, -N(C1-4alkil)2, -NHR<10d>, -NR<10c>R<10d>, cijano, -CF3, -C(=O)-NH2, -C(=O)-NH-C1-4alkil, -C(=O)-C1-4alkil, C1-4alkiloksi, -C(=O)-O-C1-4alkil, C3-6cikloalkil, -O-C3-6cikloalkil, -NH-C3-6cikloalkil, -N(C3-6cikloalkil)2, C2-6alkenil, C1-4alkil supstituisan jednim C1-4alkiloksi i C1-4alkil opciono supstituisan jednim -NR<10a>R<10b>; Ar is optionally substituted with one, two, three or four substituents each independently selected from the group consisting of halo, -OH, -NH2, -NH-C1-4alkyl, -N(C1-4alkyl)2, -NHR<10d>, -NR<10c>R<10d>, cyano, -CF3, -C(=O)-NH2, -C(=O)-NH-C1-4alkyl, -C(=O)-C1-4alkyl, C1-4alkyloxy, -C(=O)-O-C1-4alkyl, C3-6cycloalkyl, -O-C3-6cycloalkyl, -NH-C3-6cycloalkyl, -N(C3-6cycloalkyl)2, C2-6alkenyl, C1-4alkyl substituted with one C1-4alkyloxy and C1-4alkyl optionally substituted with one -NR<10a>R<10b>;

R<10a>i R<10b>svaki nezavisno predstavlja vodonik ili C1-4alkil; R<10a> and R<10b> each independently represents hydrogen or C1-4alkyl;

R<10c>i R<10d>svaki nezavisno predstavlja C3-6cikloalkil; R<13>; R<14>; C3-6cikloalkil supstituisan sa jednim, dva ili tri supstituenta od kojih je svaki nezavisno izabran iz grupe koju čine halo, -OH i -O-C1-4alkil; C1-4alkil supstituisan sa jednim, dva ili tri supstituenta od kojih je svaki nezavisno izabran iz grupe koju čine halo, -OH i -O-C1-R<10c> and R<10d> each independently represents C3-6cycloalkyl; R<13>; R<14>; C3-6cycloalkyl substituted with one, two or three substituents each independently selected from the group consisting of halo, -OH and -O-C1-4alkyl; C1-4alkyl substituted with one, two or three substituents each independently selected from the group consisting of halo, -OH and -O-C1-

4alkil; ili C1-4alkil supstituisan jednim supstituentom izabranim iz grupe koju čine C3-4alkyl; or C1-4alkyl substituted with one substituent selected from the group consisting of C3-

6cikloalkil, R<13>i R<14>; 6cycloalkyl, R<13> and R<14>;

R<13>predstavlja 4- do 7-člani monociklični aromatični prsten koji sadrži jedan, dva ili tri heteroatoma, svaki nezavisno izabran od O, S, S(=O)pi N; ili 6- do 11-člani biciklični kondenzovani aromatični prsten koji sadrži jedan, dva ili tri heteroatoma, svaki nezavisno izabran od O, S, S(=O)pi N; R<13>represents a 4- to 7-membered monocyclic aromatic ring containing one, two or three heteroatoms, each independently selected from O, S, S(=O) and N; or a 6- to 11-membered bicyclic fused aromatic ring containing one, two or three heteroatoms, each independently selected from O, S, S(=O) and N;

navedeni 4- do 7-člani monociklični aromatični prsten ili 6- do 11-člani biciklični kondenzovani aromatični prsten je opciono supstituisan sa jednim ili dva supstituenta izabrana iz grupe koju čini C1-4alkil; said 4- to 7-membered monocyclic aromatic ring or 6- to 11-membered bicyclic fused aromatic ring is optionally substituted with one or two substituents selected from the group consisting of C1-4alkyl;

p predstavlja 1 ili 2; p represents 1 or 2;

R<14>predstavlja fenil opciono supstituisan sa jednim, dva ili tri supstituenta od kojih je svaki nezavisno izabran iz grupe koju čini halo; R<14>represents phenyl optionally substituted with one, two or three substituents each independently selected from the group consisting of halo;

2 2

Het predstavlja biciklični aromatični heterociklični sistem prstenova izabran iz grupe koju čine (a-1), (a-2), (a-3), (a-4) i (a-5): Het represents a bicyclic aromatic heterocyclic ring system selected from the group consisting of (a-1), (a-2), (a-3), (a-4) and (a-5):

R<3a>, R<3b>, R<3c>, R<3d>i R<3e>svaki nezavisno predstavlja vodonik, halo, -NR<7a>R<7b>, C1-4alkil, C2-4alkenil, C3-6cikloalkil, -OH ili -O-C1-4alkil; R<3a>, R<3b>, R<3c>, R<3d>and R<3e> each independently represents hydrogen, halo, -NR<7a>R<7b>, C1-4alkyl, C2-4alkenyl, C3-6cycloalkyl, -OH or -O-C1-4alkyl;

R<7a>predstavlja vodonik; R<7a> represents hydrogen;

R<7b>predstavlja vodonik, C3-6cikloalkil, ili C1-4alkil; R<7b>represents hydrogen, C3-6cycloalkyl, or C1-4alkyl;

R<4a>, R<4b>, R<4c>, R<4d>, R<4e>, R<4f>i R<4g>svaki nezavisno predstavlja vodonik, halo, -NR<8a>R<8b>, ili C1-4alkil; R<4a>, R<4b>, R<4c>, R<4d>, R<4e>, R<4f> and R<4g> each independently represents hydrogen, halo, -NR<8a>R<8b>, or C1-4alkyl;

R<8a>i R<8b>svaki nezavisno predstavlja vodonik ili C1-4alkil; R<8a> and R<8b> each independently represents hydrogen or C1-4alkyl;

Q<1>predstavlja CR<6a>; Q<1>represents CR<6a>;

Q<2>predstavlja CR<6b>; Q<2>represents CR<6b>;

Q<3>predstavlja N ili CR<6c>; Q<3>represents N or CR<6c>;

Q<4>predstavlja N ili CR<6d>; Q<4>represents N or CR<6d>;

pod uslovom da najviše jedan od Q<3>i Q<4>predstavlja N; provided that at most one of Q<3> and Q<4> represents N;

2 2

Q<8>predstavlja N ili CR<6g>; Q<8> represents N or CR<6g>;

Q<9>predstavlja N ili CR<6h>; Q<9> represents N or CR<6h>;

Q<10>predstavlja N ili CR<6i>; Q<10>represents N or CR<6i>;

Q<11>predstavlja N ili CR<6j>; Q<11> represents N or CR<6j>;

Q<5>predstavlja CR<3d>; Q<6>predstavlja N; i Q<7>predstavlja CR<4f>; ili Q<5> represents CR<3d>; Q<6>represents N; and Q<7>represents CR<4f>; or

Q<5>predstavlja CR<3d>; Q<6>predstavlja CR<4e>; i Q<7>predstavlja N; ili Q<5> represents CR<3d>; Q<6>represents CR<4e>; and Q<7>represents N; or

Q<5>predstavlja N; Q<6>predstavlja CR<4e>; i Q<7>predstavlja CR<4f>; ili Q<5>represents N; Q<6>represents CR<4e>; and Q<7>represents CR<4f>; or

Q<5>predstavlja N; Q<6>predstavlja CR<4e>; i Q<7>predstavlja N; ili Q<5>represents N; Q<6>represents CR<4e>; and Q<7>represents N; or

Q<5>predstavlja N; Q<6>predstavlja N; i Q<7>predstavlja CR<4f>; ili Q<5>represents N; Q<6>represents N; and Q<7>represents CR<4f>; or

Q<5>predstavlja N; Q<6>predstavlja N; i Q<7>predstavlja N; Q<5>represents N; Q<6>represents N; and Q<7>represents N;

R<6a>, R<6b>, R<6c>, R<6d>, R<6e>, R<6f>, R<6g>, R<6h>, R<6i>i R<6j>svaki nezavisno predstavlja vodonik, halogen, C1-4alkil, -NR<9a>R<9b>, ili C1-4alkil supstituisan sa jednim, dva ili tri halo atoma; R<6a>, R<6b>, R<6c>, R<6d>, R<6e>, R<6f>, R<6g>, R<6h>, R<6i> and R<6j> each independently represents hydrogen, halogen, C1-4alkyl, -NR<9a>R<9b>, or C1-4alkyl substituted with one, two or three halo atoms;

R<9a>i R<9b>svaki nezavisno predstavlja vodonik ili C1-4alkil; R<9a> and R<9b> each independently represents hydrogen or C1-4alkyl;

i njegovim farmaceutski prihvatljivim adicionim solima i solvatima. and pharmaceutically acceptable addition salts and solvates thereof.

[0085] U jednom otelotvorenju, predmetni pronalazak se bavi novim jedinjenjima formule (I), pri čemu [0085] In one embodiment, the present invention relates to novel compounds of formula (I), wherein

R<1>predstavlja vodonik ili -C(=O)-C1-4alkil; R<1> represents hydrogen or -C(=O)-C1-4alkyl;

R<2>predstavlja vodonik ili -C(=O)-C1-4alkil; R<2> represents hydrogen or -C(=O)-C1-4alkyl;

2 2

Y predstavlja -CH2- ili -CF2-; Y represents -CH2- or -CF2-;

Z predstavlja -CH2-, -X-CR<5a>R<5b>-, -CR<5c>=CR<5d>-, -CR<5e>R<5g>-CR<5f>R<5h>-, -C≡C-, -O-, ili -CR<5a>R<5b>-X-; Z represents -CH2-, -X-CR<5a>R<5b>-, -CR<5c>=CR<5d>-, -CR<5e>R<5g>-CR<5f>R<5h>-, -C≡C-, -O-, or -CR<5a>R<5b>-X-;

R<5a>, R<5b>, R<5c>, R<5d>, R<5e>, R<5f>, R<5g>i R<5h>svaki nezavisno predstavlja vodonik ili C1-4alkil; R<5a>, R<5b>, R<5c>, R<5d>, R<5e>, R<5f>, R<5g> and R<5h> each independently represents hydrogen or C1-4 alkyl;

X predstavlja -O-, -S-, ili -NR<11>-; X represents -O-, -S-, or -NR<11>-;

R<11>predstavlja vodonik, C1-4alkil, ili C1-4alkil supstituisan jednim supstituentom izabranim iz grupe koju čine -OH, -O-C1-4alkil, R<12>, -NH2, -NH-C1-4alkil i -N(C1-4alkil)2; R<11> represents hydrogen, C1-4alkyl, or C1-4alkyl substituted with one substituent selected from the group consisting of -OH, -O-C1-4alkyl, R<12>, -NH2, -NH-C1-4alkyl and -N(C1-4alkyl)2;

R<12>predstavlja 4-, 5-, 6- ili 7-člani heterociklični prsten koji sadrži jedan atom azota i opciono jedan atom kiseonika, pri čemu je navedeni 4-, 5-, 6- ili 7-člani heterociklični prsten povezan sa ostatkom molekula preko atoma azota prstena; R<12>represents a 4-, 5-, 6- or 7-membered heterocyclic ring containing one nitrogen atom and optionally one oxygen atom, wherein said 4-, 5-, 6- or 7-membered heterocyclic ring is connected to the rest of the molecule via a nitrogen atom of the ring;

Ar predstavlja 10-člani biciklični aromatični sistem prstenova koji se sastoji od dva kondenzovana 6-člana prstena, Ar represents a 10-membered bicyclic aromatic ring system consisting of two fused 6-membered rings,

pri čemu je najmanje 1 atom ugljenika prstena B zamenjen atomom azota; wherein at least 1 carbon atom of ring B is replaced by a nitrogen atom;

pri čemu je opciono 1 dodatni atom ugljenika prstena A ili prstena B zamenjen atomom azota, pod uslovom da, kada atom azota zamenjuje jedan od dva kondenzovana atoma ugljenika, karbonilna grupa je prisutna u navedenom bicikličnom aromatičnom sistemu prstenova; wherein optionally 1 additional carbon atom of ring A or ring B is replaced by a nitrogen atom, provided that, when the nitrogen atom replaces one of the two fused carbon atoms, a carbonyl group is present in said bicyclic aromatic ring system;

Ar je opciono supstituisan sa jednim, dva, tri ili četiri supstituenta od kojih je svaki nezavisno izabran iz grupe koju čine halo, -OH, -NH2, -NH-C1-4alkil, -N(C1-4alkil)2, - Ar is optionally substituted with one, two, three or four substituents each independently selected from the group consisting of halo, -OH, -NH2, -NH-C1-4alkyl, -N(C1-4alkyl)2, -

2 2

NHR<10d>, -NR<10c>R<10d>, cijano, -CF3, -C(=O)-NH2, -C(=O)-NH-C1-4alkil, -C(=O)-C1-4alkil, C1-4alkiloksi, -C(=O)-O-C1-4alkil, C3-6cikloalkil, C2-6alkenil, C1-4alkil supstituisan jednim C1-4alkiloksi i C1-4alkil opciono supstituisan jednim - NR<10a>R<10b>; NHR<10d>, -NR<10c>R<10d>, cyano, -CF3, -C(=O)-NH2, -C(=O)-NH-C1-4alkyl, -C(=O)-C1-4alkyl, C1-4alkyloxy, -C(=O)-O-C1-4alkyl, C3-6cycloalkyl, C2-6alkenyl, C1-4alkyl substituted with one C1-4alkyloxy and C1-4alkyl optionally substituted by one - NR<10a>R<10b>;

R<10a>i R<10b>svaki nezavisno predstavlja vodonik ili C1-4alkil; R<10a> and R<10b> each independently represents hydrogen or C1-4alkyl;

R<10c>i R<10d>svaki nezavisno predstavlja C3-6cikloalkil; C3-6cikloalkil supstituisan sa jednim, dva ili tri supstituenta od kojih je svaki nezavisno izabran iz grupe koju čine halo, -OH i -O-C1-4alkil; C1-4alkil supstituisan sa jednim, dva ili tri supstituenta od kojih je svaki nezavisno izabran iz grupe koju čine halo, -OH i -O-C1-4alkil; ili C1-4alkil supstituisan jednim supstituentom izabranim iz grupe koju čine C3-6cikloalkil, R<13>i R<14>; R<10c> and R<10d> each independently represents C3-6cycloalkyl; C3-6cycloalkyl substituted with one, two or three substituents each independently selected from the group consisting of halo, -OH and -O-C1-4alkyl; C1-4alkyl substituted with one, two or three substituents each independently selected from the group consisting of halo, -OH and -O-C1-4alkyl; or C1-4alkyl substituted with one substituent selected from the group consisting of C3-6cycloalkyl, R<13> and R<14>;

R<13>predstavlja 4- do 7-člani monociklični aromatični prsten koji sadrži jedan, dva ili tri heteroatoma, svaki nezavisno izabran od O, S, S(=O)pi N; ili 6- do 11-člani biciklični kondenzovani aromatični prsten koji sadrži jedan, dva ili tri heteroatoma, svaki nezavisno izabran od O, S, S(=O)pi N; R<13>represents a 4- to 7-membered monocyclic aromatic ring containing one, two or three heteroatoms, each independently selected from O, S, S(=O) and N; or a 6- to 11-membered bicyclic fused aromatic ring containing one, two or three heteroatoms, each independently selected from O, S, S(=O) and N;

navedeni 4- do 7-člani monociklični aromatični prsten ili 6- do 11-člani biciklični kondenzovani aromatični prsten je opciono supstituisan sa jednim ili dva supstituenta izabrana iz grupe koju čini C1-4alkil; said 4- to 7-membered monocyclic aromatic ring or 6- to 11-membered bicyclic fused aromatic ring is optionally substituted with one or two substituents selected from the group consisting of C1-4alkyl;

p predstavlja 1 ili 2; p represents 1 or 2;

R<14>predstavlja fenil opciono supstituisan sa jednim, dva ili tri supstituenta od kojih je svaki nezavisno izabran iz grupe koju čini halo; R<14>represents phenyl optionally substituted with one, two or three substituents each independently selected from the group consisting of halo;

Het predstavlja biciklični aromatični heterociklični sistem prstenova izabran iz grupe koju čine (a-1), (a-2) i (a-3): Het represents a bicyclic aromatic heterocyclic ring system selected from the group consisting of (a-1), (a-2) and (a-3):

2 2

R<3a>, R<3b>i R<3c>svaki nezavisno predstavlja vodonik, halo, -NR<7a>R<7b>, C1-4alkil ili -O-C1-4alkil; R<3a>, R<3b> and R<3c> each independently represents hydrogen, halo, -NR<7a>R<7b>, C1-4alkyl or -O-C1-4alkyl;

R<7a>predstavlja vodonik; R<7a> represents hydrogen;

R<7b>predstavlja vodonik ili C1-4alkil; R<7b>represents hydrogen or C1-4alkyl;

R<4a>, R<4b>i R<4c>svaki nezavisno predstavlja vodonik, halo, -NR<8a>R<8b>, ili C1-4alkil; R<8a>i R<8b>svaki nezavisno predstavlja vodonik ili C1-4alkil; R<4a>, R<4b> and R<4c> each independently represents hydrogen, halo, -NR<8a>R<8b>, or C1-4alkyl; R<8a> and R<8b> each independently represents hydrogen or C1-4alkyl;

Q<1>predstavlja N ili CR<6a>; Q<1>represents N or CR<6a>;

Q<2>predstavlja N ili CR<6b>; Q<2>represents N or CR<6b>;

Q<3>predstavlja N ili CR<6c>; Q<3>represents N or CR<6c>;

Q<4>predstavlja N ili CR<6d>; Q<4>represents N or CR<6d>;

pod uslovom da najviše jedan od Q<3>i Q<4>predstavlja N; provided that at most one of Q<3> and Q<4> represents N;

R<6a>, R<6b>, R<6c>, R<6d>, R<6e>i R<6f>svaki nezavisno predstavlja vodonik, halogen, C1-4alkil, -NR<9a>R<9b>, ili C1-4alkil supstituisan sa jednim, dva ili tri halo atoma; R<6a>, R<6b>, R<6c>, R<6d>, R<6e> and R<6f> each independently represents hydrogen, halogen, C1-4alkyl, -NR<9a>R<9b>, or C1-4alkyl substituted with one, two or three halo atoms;

R<9a>i R<9b>svaki nezavisno predstavlja vodonik ili C1-4alkil; R<9a> and R<9b> each independently represents hydrogen or C1-4alkyl;

i njegovim farmaceutski prihvatljivim adicionim solima i solvatima. and pharmaceutically acceptable addition salts and solvates thereof.

[0086] U jednom otelotvorenju, predmetni pronalazak se bavi novim jedinjenjima formule (I), pri čemu [0086] In one embodiment, the present invention relates to novel compounds of formula (I), wherein

R<1>predstavlja vodonik ili -C(=O)-C1-4alkil; R<1> represents hydrogen or -C(=O)-C1-4alkyl;

R<2>predstavlja vodonik ili -C(=O)-C1-4alkil; R<2> represents hydrogen or -C(=O)-C1-4alkyl;

Y predstavlja -CH2- ili -CF2-; Y represents -CH2- or -CF2-;

Z predstavlja -CH2-, -X-CR<5a>R<5b>-, -CR<5c>=CR<5d>-, -CR<5e>R<5g>-CR<5f>R<5h>-, -C≡C-, -O-, ili -CR<5a>R<5b>-X-; Z represents -CH2-, -X-CR<5a>R<5b>-, -CR<5c>=CR<5d>-, -CR<5e>R<5g>-CR<5f>R<5h>-, -C≡C-, -O-, or -CR<5a>R<5b>-X-;

R<5a>, R<5b>, R<5c>, R<5d>, R<5e>, R<5f>, R<5g>i R<5h>svaki nezavisno predstavlja vodonik ili C1-4alkil; R<5a>, R<5b>, R<5c>, R<5d>, R<5e>, R<5f>, R<5g> and R<5h> each independently represents hydrogen or C1-4 alkyl;

X predstavlja -O-, -S-, ili -NR<11>-; X represents -O-, -S-, or -NR<11>-;

R<11>predstavlja vodonik, C1-4alkil, ili C1-4alkil supstituisan jednim supstituentom izabranim iz grupe koju čine -OH, -O-C1-4alkil, R<12>, -NH2, -NH-C1-4alkil i -N(C1-4alkil)2; R<11> represents hydrogen, C1-4alkyl, or C1-4alkyl substituted with one substituent selected from the group consisting of -OH, -O-C1-4alkyl, R<12>, -NH2, -NH-C1-4alkyl and -N(C1-4alkyl)2;

R<12>predstavlja 4-, 5-, 6- ili 7-člani heterociklični prsten koji sadrži jedan atom azota i opciono jedan atom kiseonika, pri čemu je navedeni 4-, 5-, 6- ili 7-člani heterociklični prsten povezan sa ostatkom molekula preko atoma azota prstena; R<12>represents a 4-, 5-, 6- or 7-membered heterocyclic ring containing one nitrogen atom and optionally one oxygen atom, wherein said 4-, 5-, 6- or 7-membered heterocyclic ring is connected to the rest of the molecule via a nitrogen atom of the ring;

Ar predstavlja 10-člani biciklični aromatični sistem prstenova koji se sastoji od dva kondenzovana 6-člana prstena, Ar represents a 10-membered bicyclic aromatic ring system consisting of two fused 6-membered rings,

pri čemu je najmanje 1 atom ugljenika prstena B zamenjen atomom azota; wherein at least 1 carbon atom of ring B is replaced by a nitrogen atom;

1 1

pri čemu je opciono 1 dodatni atom ugljenika prstena A ili prstena B zamenjen atomom azota, pod uslovom da, kada atom azota zamenjuje jedan od dva kondenzovana atoma ugljenika, karbonilna grupa je prisutna u navedenom bicikličnom aromatičnom sistemu prstenova; wherein optionally 1 additional carbon atom of ring A or ring B is replaced by a nitrogen atom, provided that, when the nitrogen atom replaces one of the two fused carbon atoms, a carbonyl group is present in said bicyclic aromatic ring system;

Ar je opciono supstituisan sa jednim, dva, tri ili četiri supstituenta od kojih je svaki nezavisno izabran iz grupe koju čine halo, -OH, -NH2, -NH-C1-4alkil, -N(C1-4alkil)2, cijano, -CF3, -C(=O)-NH-C1-4alkil, -C(=O)-C1-4alkil, C1-4alkiloksi i C1-4alkil opciono supstituisan jednim -NR<10a>R<10b>; Ar is optionally substituted with one, two, three or four substituents each independently selected from the group consisting of halo, -OH, -NH2, -NH-C1-4alkyl, -N(C1-4alkyl)2, cyano, -CF3, -C(=O)-NH-C1-4alkyl, -C(=O)-C1-4alkyl, C1-4alkyloxy and C1-4alkyl optionally substituted with one -NR<10a>R<10b>;

R<10a>i R<10b>svaki nezavisno predstavlja vodonik ili C1-4alkil; R<10a> and R<10b> each independently represents hydrogen or C1-4alkyl;

Het predstavlja biciklični aromatični heterociklični sistem prstenova izabran iz grupe koju čine (a-1), (a-2) i (a-3): Het represents a bicyclic aromatic heterocyclic ring system selected from the group consisting of (a-1), (a-2) and (a-3):

R<3a>, R<3b>i R<3c>svaki nezavisno predstavlja vodonik, halo, -NR<7a>R<7b>, ili -O-C1-4alkil; R<3a>, R<3b> and R<3c> each independently represents hydrogen, halo, -NR<7a>R<7b>, or -O-C1-4alkyl;

R<7a>predstavlja vodonik; R<7a> represents hydrogen;

R<7b>predstavlja vodonik ili C1-4alkil; R<7b>represents hydrogen or C1-4alkyl;

R<4a>, R<4b>i R<4c>svaki nezavisno predstavlja vodonik, halo, -NR<8a>R<8b>, ili C1-4alkil; R<8a>i R<8b>svaki nezavisno predstavlja vodonik ili C1-4alkil; R<4a>, R<4b> and R<4c> each independently represents hydrogen, halo, -NR<8a>R<8b>, or C1-4alkyl; R<8a> and R<8b> each independently represents hydrogen or C1-4alkyl;

Q<1>predstavlja N ili CR<6a>; Q<1>represents N or CR<6a>;

2 2

Q<2>predstavlja N ili CR<6b>; Q<2>represents N or CR<6b>;

Q<3>predstavlja N ili CR<6c>; Q<3>represents N or CR<6c>;

Q<4>predstavlja N ili CR<6d>; Q<4>represents N or CR<6d>;

pod uslovom da najviše jedan od Q<3>i Q<4>predstavlja N; provided that at most one of Q<3> and Q<4> represents N;

R<6a>, R<6b>, R<6c>, R<6d>, R<6e>i R<6f>svaki nezavisno predstavlja vodonik, halogen, C1-4alkil, -NR<9a>R<9b>, ili C1-4alkil supstituisan sa jednim, dva ili tri halo atoma; R<6a>, R<6b>, R<6c>, R<6d>, R<6e> and R<6f> each independently represents hydrogen, halogen, C1-4alkyl, -NR<9a>R<9b>, or C1-4alkyl substituted with one, two or three halo atoms;

R<9a>i R<9b>svaki nezavisno predstavlja vodonik ili C1-4alkil; R<9a> and R<9b> each independently represents hydrogen or C1-4alkyl;

i njegovim farmaceutski prihvatljivim adicionim solima i solvatima. and pharmaceutically acceptable addition salts and solvates thereof.

[0087] U jednom otelotvorenju, predmetni pronalazak se bavi novim jedinjenjima formule (I), pri čemu [0087] In one embodiment, the present invention relates to novel compounds of formula (I), wherein

R<1>predstavlja vodonik ili -C(=O)-C1-4alkil; R<1> represents hydrogen or -C(=O)-C1-4alkyl;

R<2>predstavlja vodonik ili -C(=O)-C1-4alkil; R<2> represents hydrogen or -C(=O)-C1-4alkyl;

Y predstavlja -CH2- ili -CF2-; Y represents -CH2- or -CF2-;

Z predstavlja -CH2-, -X-CR<5a>R<5b>-, -CR<5c>=CR<5d>-, -CR<5e>R<5g>-CR<5f>R<5h>-, -C≡C-, -O-, ili -CR<5a>R<5b>-X-; Z represents -CH2-, -X-CR<5a>R<5b>-, -CR<5c>=CR<5d>-, -CR<5e>R<5g>-CR<5f>R<5h>-, -C≡C-, -O-, or -CR<5a>R<5b>-X-;

R<5a>, R<5b>, R<5c>, R<5d>, R<5e>, R<5f>, R<59>, i R<5h>svaki nezavisno predstavlja vodonik ili C1-4alkil; R<5a>, R<5b>, R<5c>, R<5d>, R<5e>, R<5f>, R<59>, and R<5h> each independently represents hydrogen or C1-4alkyl;

X predstavlja -O-, -S-, ili -NR<11>-; X represents -O-, -S-, or -NR<11>-;

R<11>predstavlja vodonik, C1-4alkil, ili C1-4alkil supstituisan jednim supstituentom izabranim iz grupe koju čine -OH, -O-C1-4alkil, R<12>, -NH2, -NH-C1-4alkil i -N(C1-4alkil)2; R<12>predstavlja 4-, 5-, 6- ili 7-člani heterociklični prsten koji sadrži jedan atom azota i opciono jedan atom kiseonika, pri čemu je navedeni 4-, 5-, 6- ili 7-člani heterociklični prsten povezan sa ostatkom molekula preko atoma azota prstena; R<11> represents hydrogen, C1-4alkyl, or C1-4alkyl substituted with one substituent selected from the group consisting of -OH, -O-C1-4alkyl, R<12>, -NH2, -NH-C1-4alkyl and -N(C1-4alkyl)2; R<12>represents a 4-, 5-, 6- or 7-membered heterocyclic ring containing one nitrogen atom and optionally one oxygen atom, wherein said 4-, 5-, 6- or 7-membered heterocyclic ring is connected to the rest of the molecule via a nitrogen atom of the ring;

Ar predstavlja 10-člani biciklični aromatični sistem prstenova koji se sastoji od dva kondenzovana 6-člana prstena, Ar represents a 10-membered bicyclic aromatic ring system consisting of two fused 6-membered rings,

pri čemu je najmanje 1 atom ugljenika prstena B zamenjen atomom azota; wherein at least 1 carbon atom of ring B is replaced by a nitrogen atom;

pri čemu je opciono 1 dodatni atom ugljenika prstena A ili prstena B zamenjen atomom azota, pod uslovom da, kada atom azota zamenjuje jedan od dva kondenzovana atoma ugljenika, karbonilna grupa je prisutna u navedenom bicikličnom aromatičnom sistemu prstenova; wherein optionally 1 additional carbon atom of ring A or ring B is replaced by a nitrogen atom, provided that, when the nitrogen atom replaces one of the two fused carbon atoms, a carbonyl group is present in said bicyclic aromatic ring system;

Ar je opciono supstituisan sa jednim, dva, tri ili četiri supstituenta od kojih je svaki nezavisno izabran iz grupe koju čine halo, -OH, -NH2, -NH-C1-4alkil, -N(C1-4alkil)2, -NHR<10d>, -NR<10c>R<10d>, cijano, -CF3, -C(=O)-NH2, -C(=O)-NH-C1-4alkil, -C(=O)-C1-4alkil, C1-4alkiloksi, -C(=O)-O-C1-4alkil, C3-6cikloalkil, -O-C3-6cikloalkil, -NH-C3-6cikloalkil, -N(C3-6cikloalkil)2, C2-6alkenil, C1-4alkil supstituisan jednim C1-4alkiloksi i C1-4alkil opciono supstituisan jednim -NR<10a>R<10b>; Ar is optionally substituted with one, two, three or four substituents each independently selected from the group consisting of halo, -OH, -NH2, -NH-C1-4alkyl, -N(C1-4alkyl)2, -NHR<10d>, -NR<10c>R<10d>, cyano, -CF3, -C(=O)-NH2, -C(=O)-NH-C1-4alkyl, -C(=O)-C1-4alkyl, C1-4alkyloxy, -C(=O)-O-C1-4alkyl, C3-6cycloalkyl, -O-C3-6cycloalkyl, -NH-C3-6cycloalkyl, -N(C3-6cycloalkyl)2, C2-6alkenyl, C1-4alkyl substituted with one C1-4alkyloxy and C1-4alkyl optionally substituted with one -NR<10a>R<10b>;

R<10a>i R<10b>svaki nezavisno predstavlja vodonik ili C1-4alkil; R<10a> and R<10b> each independently represents hydrogen or C1-4alkyl;

R<10c>i R<10d>svaki nezavisno predstavlja C3-6cikloalkil; R<13>; R<14>; C3-6cikloalkil supstituisan sa jednim, dva ili tri supstituenta od kojih je svaki nezavisno izabran iz grupe koju čine halo, -OH i -O-C1-4alkil; C1-4alkil supstituisan sa jednim, dva ili tri supstituenta od kojih je svaki nezavisno izabran iz grupe koju čine halo, -OH i -O-C1-R<10c> and R<10d> each independently represents C3-6cycloalkyl; R<13>; R<14>; C3-6cycloalkyl substituted with one, two or three substituents each independently selected from the group consisting of halo, -OH and -O-C1-4alkyl; C1-4alkyl substituted with one, two or three substituents each independently selected from the group consisting of halo, -OH and -O-C1-

4alkil; ili C1-4alkil supstituisan jednim supstituentom izabranim iz grupe koju čine C3-4alkyl; or C1-4alkyl substituted with one substituent selected from the group consisting of C3-

6cikloalkil, R<13>i R<14>; 6cycloalkyl, R<13> and R<14>;

4 4

R<13>predstavlja 4- do 7-člani monociklični aromatični prsten koji sadrži jedan, dva ili tri heteroatoma, svaki nezavisno izabran od O, S, S(=O)pi N; ili 6- do 11-člani biciklični kondenzovani aromatični prsten koji sadrži jedan, dva ili tri heteroatoma, svaki nezavisno izabran od O, S, S(=O)pi N; R<13>represents a 4- to 7-membered monocyclic aromatic ring containing one, two or three heteroatoms, each independently selected from O, S, S(=O) and N; or a 6- to 11-membered bicyclic fused aromatic ring containing one, two or three heteroatoms, each independently selected from O, S, S(=O) and N;

navedeni 4- do 7-člani monociklični aromatični prsten ili 6- do 11-člani biciklični kondenzovani aromatični prsten je opciono supstituisan sa jednim ili dva supstituenta izabrana iz grupe koju čini C1-4alkil; said 4- to 7-membered monocyclic aromatic ring or 6- to 11-membered bicyclic fused aromatic ring is optionally substituted with one or two substituents selected from the group consisting of C1-4alkyl;

p predstavlja 1 ili 2; p represents 1 or 2;

R<14>predstavlja fenil opciono supstituisan sa jednim, dva ili tri supstituenta od kojih je svaki nezavisno izabran iz grupe koju čini halo; R<14>represents phenyl optionally substituted with one, two or three substituents each independently selected from the group consisting of halo;

Het predstavlja biciklični aromatični heterociklični sistem prstenova izabran iz grupe koju čine (a-1), (a-2), (a-3), (a-4) i (a-5): Het represents a bicyclic aromatic heterocyclic ring system selected from the group consisting of (a-1), (a-2), (a-3), (a-4) and (a-5):

R<3a>, R<3b>, R<3c>, R<3d>i R<3e>svaki nezavisno predstavlja vodonik, halo, -NR<7a>R<7b>, C1-4alkil, C2-4alkenil, C3-6cikloalkil, -OH ili -O-C1-4alkil; R<3a>, R<3b>, R<3c>, R<3d>and R<3e> each independently represents hydrogen, halo, -NR<7a>R<7b>, C1-4alkyl, C2-4alkenyl, C3-6cycloalkyl, -OH or -O-C1-4alkyl;

R<7a>predstavlja vodonik; R<7a> represents hydrogen;

R<7b>predstavlja vodonik, C3-6cikloalkil, ili C1-4alkil; R<7b>represents hydrogen, C3-6cycloalkyl, or C1-4alkyl;

R<4a>, R<4b>, R<4c>, R<4d>, R<4e>, R<4f>i R<4g>svaki nezavisno predstavlja vodonik, halo, -NR<8a>R<8b>, ili C1-4alkil; R<4a>, R<4b>, R<4c>, R<4d>, R<4e>, R<4f> and R<4g> each independently represents hydrogen, halo, -NR<8a>R<8b>, or C1-4alkyl;

R<8a>i R<8b>svaki nezavisno predstavlja vodonik ili C1-4alkil; R<8a> and R<8b> each independently represents hydrogen or C1-4alkyl;

Q<1>predstavlja N ili CR<6a>; Q<1>represents N or CR<6a>;

Q<2>predstavlja N ili CR<6b>; Q<2>represents N or CR<6b>;

Q<3>predstavlja N ili CR<6c>; Q<3>represents N or CR<6c>;

Q<4>predstavlja N ili CR<6d>; Q<4>represents N or CR<6d>;

pod uslovom da najviše jedan od Q<3>i Q<4>predstavlja N; provided that at most one of Q<3> and Q<4> represents N;

Q<8>predstavlja N ili CR<6g>; Q<8> represents N or CR<6g>;

Q<9>predstavlja N ili CR<6h>; Q<9> represents N or CR<6h>;

Q<10>predstavlja N ili CR<6i>; Q<10>represents N or CR<6i>;

Q<11>predstavlja N ili CR<6j>; Q<11> represents N or CR<6j>;

Q<5>predstavlja CR<3d>; Q<6>predstavlja N; i Q<7>predstavlja CR<4f>; ili Q<5> represents CR<3d>; Q<6>represents N; and Q<7>represents CR<4f>; or

Q<5>predstavlja CR<3d>; Q<6>predstavlja CR<4e>; i Q<7>predstavlja N; ili Q<5> represents CR<3d>; Q<6>represents CR<4e>; and Q<7>represents N; or

Q<5>predstavlja N; Q<6>predstavlja CR<4e>; i Q<7>predstavlja CR<4f>; ili Q<5>represents N; Q<6>represents CR<4e>; and Q<7>represents CR<4f>; or

Q<5>predstavlja N; Q<6>predstavlja CR<4e>; i Q<7>predstavlja N; ili Q<5>represents N; Q<6>represents CR<4e>; and Q<7>represents N; or

Q<5>predstavlja N; Q<6>predstavlja N; i Q<7>predstavlja CR<4f>; ili Q<5>represents N; Q<6>represents N; and Q<7>represents CR<4f>; or

Q<5>predstavlja N; Q<6>predstavlja N; i Q<7>predstavlja N; Q<5>represents N; Q<6>represents N; and Q<7>represents N;

R<6a>, R<6b>, R<6c>, R<6d>, R<6e>, R<6f>, R<6g>, R<6h>, R<6i>i R<6j>svaki nezavisno predstavlja vodonik, halogen, C1-4alkil, -NR<9a>R<9b>, ili C1-4alkil supstituisan sa jednim, dva ili tri halo atoma; R<6a>, R<6b>, R<6c>, R<6d>, R<6e>, R<6f>, R<6g>, R<6h>, R<6i> and R<6j> each independently represents hydrogen, halogen, C1-4alkyl, -NR<9a>R<9b>, or C1-4alkyl substituted with one, two or three halo atoms;

R<9a>i R<9b>svaki nezavisno predstavlja vodonik ili C1-4alkil; R<9a> and R<9b> each independently represents hydrogen or C1-4alkyl;

i njegovim farmaceutski prihvatljivim adicionim solima i solvatima. and pharmaceutically acceptable addition salts and solvates thereof.

[0088] U jednom otelotvorenju, predmetni pronalazak se bavi novim jedinjenjima formule (I), pri čemu [0088] In one embodiment, the present invention relates to novel compounds of formula (I), wherein

R<1>predstavlja vodonik; R<1> represents hydrogen;

R<2>predstavlja vodonik; R<2> represents hydrogen;

Y predstavlja -CH2- ili -CF2-; Y represents -CH2- or -CF2-;

Z predstavlja -CH2-, -X-CR<5a>R<5b>-, -CR<5c>=CR<5d>-, -CR<5e>R<5g>-CR<5f>R<5h>-, -C≡C-, -O-, ili -CR<5a>R<5b>-X-; Z represents -CH2-, -X-CR<5a>R<5b>-, -CR<5c>=CR<5d>-, -CR<5e>R<5g>-CR<5f>R<5h>-, -C≡C-, -O-, or -CR<5a>R<5b>-X-;

R<5a>, R<5b>, R<5c>, R<5d>, R<5e>, R<5f>, R<5g>i R<5h>svaki nezavisno predstavlja vodonik ili C1-4alkil; R<5a>, R<5b>, R<5c>, R<5d>, R<5e>, R<5f>, R<5g> and R<5h> each independently represents hydrogen or C1-4 alkyl;

X predstavlja -O-, -S-, ili -NR<11>-; X represents -O-, -S-, or -NR<11>-;

R<11>predstavlja vodonik, C1-4alkil, ili C1-4alkil supstituisan jednim supstituentom izabranim iz grupe koju čine -OH, -O-C1-4alkil, R<12>, -NH2, -NH-C1-4alkil i -N(C1-4alkil)2; R<11> represents hydrogen, C1-4alkyl, or C1-4alkyl substituted with one substituent selected from the group consisting of -OH, -O-C1-4alkyl, R<12>, -NH2, -NH-C1-4alkyl and -N(C1-4alkyl)2;

R<12>predstavlja 4-, 5-, 6- ili 7-člani heterociklični prsten koji sadrži jedan atom azota i opciono jedan atom kiseonika, pri čemu je navedeni 4-, 5-, 6- ili 7-člani heterociklični prsten povezan sa ostatkom molekula preko atoma azota prstena; R<12>represents a 4-, 5-, 6- or 7-membered heterocyclic ring containing one nitrogen atom and optionally one oxygen atom, wherein said 4-, 5-, 6- or 7-membered heterocyclic ring is connected to the rest of the molecule via a nitrogen atom of the ring;

Ar predstavlja 10-člani biciklični aromatični sistem prstenova koji se sastoji od dva kondenzovana 6-člana prstena, Ar represents a 10-membered bicyclic aromatic ring system consisting of two fused 6-membered rings,

pri čemu je najmanje 1 atom ugljenika prstena B zamenjen atomom azota; wherein at least 1 carbon atom of ring B is replaced by a nitrogen atom;

pri čemu je opciono 1 dodatni atom ugljenika prstena A ili prstena B zamenjen atomom azota, pod uslovom da, kada atom azota zamenjuje jedan od dva kondenzovana atoma ugljenika, karbonilna grupa je prisutna u navedenom bicikličnom aromatičnom sistemu prstenova; wherein optionally 1 additional carbon atom of ring A or ring B is replaced by a nitrogen atom, provided that, when the nitrogen atom replaces one of the two fused carbon atoms, a carbonyl group is present in said bicyclic aromatic ring system;

Ar je opciono supstituisan sa jednim, dva, tri ili četiri supstituenta od kojih je svaki nezavisno izabran iz grupe koju čine halo, -OH, -NH2, -NH-C1-4alkil, -N(C1-4alkil)2, -NHR<10d>, -NR<10c>R<10d>, cijano, -CF3, -C(=O)-NH2, -C(=O)-NH-C1-4alkil, -C(=O)-C1-4alkil, C1-4alkiloksi, -C(=O)-O-C1-4alkil, C3-6cikloalkil, -O-C3-6cikloalkil, -NH-C3-6cikloalkil, -N(C3-6cikloalkil)2, C2-6alkenil, C1-4alkil supstituisan jednim C1-4alkiloksi i C1-4alkil opciono supstituisan jednim -NR<10a>R<10b>; Ar is optionally substituted with one, two, three or four substituents each independently selected from the group consisting of halo, -OH, -NH2, -NH-C1-4alkyl, -N(C1-4alkyl)2, -NHR<10d>, -NR<10c>R<10d>, cyano, -CF3, -C(=O)-NH2, -C(=O)-NH-C1-4alkyl, -C(=O)-C1-4alkyl, C1-4alkyloxy, -C(=O)-O-C1-4alkyl, C3-6cycloalkyl, -O-C3-6cycloalkyl, -NH-C3-6cycloalkyl, -N(C3-6cycloalkyl)2, C2-6alkenyl, C1-4alkyl substituted with one C1-4alkyloxy and C1-4alkyl optionally substituted with one -NR<10a>R<10b>;

R<10a>i R<10b>svaki nezavisno predstavlja vodonik ili C1-4alkil; R<10a> and R<10b> each independently represents hydrogen or C1-4alkyl;

R<10c>i R<10d>svaki nezavisno predstavlja C3-6cikloalkil; R<13>; R<14>; C3-6cikloalkil supstituisan sa jednim, dva ili tri supstituenta od kojih je svaki nezavisno izabran iz grupe koju čine halo, -OH i -O-C1-4alkil; C1-4alkil supstituisan sa jednim, dva ili tri supstituenta od kojih je svaki nezavisno izabran iz grupe koju čine halo, -OH i -O-C1-R<10c> and R<10d> each independently represents C3-6cycloalkyl; R<13>; R<14>; C3-6cycloalkyl substituted with one, two or three substituents each independently selected from the group consisting of halo, -OH and -O-C1-4alkyl; C1-4alkyl substituted with one, two or three substituents each independently selected from the group consisting of halo, -OH and -O-C1-

4alkil; ili C1-4alkil supstituisan jednim supstituentom izabranim iz grupe koju čine C3-4alkyl; or C1-4alkyl substituted with one substituent selected from the group consisting of C3-

6cikloalkil, R<13>i R<14>; 6cycloalkyl, R<13> and R<14>;

R<13>predstavlja 4- do 7-člani monociklični aromatični prsten koji sadrži jedan, dva ili tri heteroatoma, svaki nezavisno izabran od O, S, S(=O)pi N; ili 6- do 11-člani biciklični kondenzovani aromatični prsten koji sadrži jedan, dva ili tri heteroatoma, svaki nezavisno izabran od O, S, S(=O)pi N; R<13>represents a 4- to 7-membered monocyclic aromatic ring containing one, two or three heteroatoms, each independently selected from O, S, S(=O) and N; or a 6- to 11-membered bicyclic fused aromatic ring containing one, two or three heteroatoms, each independently selected from O, S, S(=O) and N;

navedeni 4- do 7-člani monociklični aromatični prsten ili 6- do 11-člani biciklični kondenzovani aromatični prsten je opciono supstituisan sa jednim ili dva supstituenta izabrana iz grupe koju čini C1-4alkil; said 4- to 7-membered monocyclic aromatic ring or 6- to 11-membered bicyclic fused aromatic ring is optionally substituted with one or two substituents selected from the group consisting of C1-4alkyl;

p predstavlja 1 ili 2; p represents 1 or 2;

R<14>predstavlja fenil opciono supstituisan sa jednim, dva ili tri supstituenta od kojih je svaki nezavisno izabran iz grupe koju čini halo; R<14>represents phenyl optionally substituted with one, two or three substituents each independently selected from the group consisting of halo;

Het predstavlja biciklični aromatični heterociklični sistem prstenova izabran iz grupe koju čine (a-1), (a-2), (a-3), (a-4) i (a-5): Het represents a bicyclic aromatic heterocyclic ring system selected from the group consisting of (a-1), (a-2), (a-3), (a-4) and (a-5):

R<3a>, R<3b>, R<3c>, R<3d>i R<3e>svaki nezavisno predstavlja vodonik, halo, -NR<7a>R<7b>, C1-4alkil, C2-4alkenil, C3-6cikloalkil, -OH ili -O-C1-4alkil; R<3a>, R<3b>, R<3c>, R<3d>and R<3e> each independently represents hydrogen, halo, -NR<7a>R<7b>, C1-4alkyl, C2-4alkenyl, C3-6cycloalkyl, -OH or -O-C1-4alkyl;

R<7a>predstavlja vodonik; R<7a> represents hydrogen;

R<7b>predstavlja vodonik, C3-6cikloalkil, ili C1-4alkil; R<7b>represents hydrogen, C3-6cycloalkyl, or C1-4alkyl;

R<4a>, R<4b>, R<4c>, R<4d>, R<4e>, R<4f>i R<4g>svaki nezavisno predstavlja vodonik, halo, -NR<8a>R<8b>, ili C1-4alkil; R<4a>, R<4b>, R<4c>, R<4d>, R<4e>, R<4f> and R<4g> each independently represents hydrogen, halo, -NR<8a>R<8b>, or C1-4alkyl;

R<8a>i R<8b>svaki nezavisno predstavlja vodonik ili C1-4alkil; R<8a> and R<8b> each independently represents hydrogen or C1-4alkyl;

Q<1>predstavlja N ili CR<6a>; Q<1>represents N or CR<6a>;

Q<2>predstavlja N ili CR<6b>; Q<2>represents N or CR<6b>;

Q<3>predstavlja N ili CR<6c>; Q<3>represents N or CR<6c>;

Q<4>predstavlja N ili CR<6d>; Q<4>represents N or CR<6d>;

pod uslovom da najviše jedan od Q<3>i Q<4>predstavlja N; provided that at most one of Q<3> and Q<4> represents N;

Q<8>predstavlja N ili CR<6g>; Q<8> represents N or CR<6g>;

Q<9>predstavlja N ili CR<6h>; Q<9> represents N or CR<6h>;

Q<10>predstavlja N ili CR<6i>; Q<10>represents N or CR<6i>;

Q<11>predstavlja N ili CR<6j>; Q<11> represents N or CR<6j>;

Q<5>predstavlja CR<3d>; Q<6>predstavlja N; i Q<7>predstavlja CR<4f>; ili Q<5> represents CR<3d>; Q<6>represents N; and Q<7>represents CR<4f>; or

Q<5>predstavlja CR<3d>; Q<6>predstavlja CR<4e>; i Q<7>predstavlja N; ili Q<5> represents CR<3d>; Q<6>represents CR<4e>; and Q<7>represents N; or

Q<5>predstavlja N; Q<6>predstavlja CR<4e>; i Q<7>predstavlja CR<4f>; ili Q<5>represents N; Q<6>represents CR<4e>; and Q<7>represents CR<4f>; or

Q<5>predstavlja N; Q<6>predstavlja CR<4e>; i Q<7>predstavlja N; ili Q<5>represents N; Q<6>represents CR<4e>; and Q<7>represents N; or

Q<5>predstavlja N; Q<6>predstavlja N; i Q<7>predstavlja CR<4f>; ili Q<5>represents N; Q<6>represents N; and Q<7>represents CR<4f>; or

Q<5>predstavlja N; Q<6>predstavlja N; i Q<7>predstavlja N; Q<5>represents N; Q<6>represents N; and Q<7>represents N;

R<6a>, R<6b>, R<6c>, R<6d>, R<6e>, R<6f>, R<6g>, R<6h>, R<6i>i R<6j>svaki nezavisno predstavlja vodonik, halogen, C1-4alkil, -NR<9a>R<9b>, ili C1-4alkil supstituisan sa jednim, dva ili tri halo atoma; R<6a>, R<6b>, R<6c>, R<6d>, R<6e>, R<6f>, R<6g>, R<6h>, R<6i> and R<6j> each independently represents hydrogen, halogen, C1-4alkyl, -NR<9a>R<9b>, or C1-4alkyl substituted with one, two or three halo atoms;

R<9a>i R<9b>svaki nezavisno predstavlja vodonik ili C1-4alkil; R<9a> and R<9b> each independently represents hydrogen or C1-4alkyl;

4 4

i njegovim farmaceutski prihvatljivim adicionim solima i solvatima. and pharmaceutically acceptable addition salts and solvates thereof.

[0089] U jednom otelotvorenju, predmetni pronalazak se bavi novim jedinjenjima formule (I), pri čemu [0089] In one embodiment, the present invention relates to novel compounds of formula (I), wherein

R<1>predstavlja vodonik; R<1> represents hydrogen;

R<2>predstavlja vodonik; R<2> represents hydrogen;

Y predstavlja -CH2- ili -CF2-; Y represents -CH2- or -CF2-;

Z predstavlja -CH2-, -X-CR<5a>R<5b>-, -CR<5c>=CR<5d>-, -CR<5e>R<5g>-CR<5f>R<5h>-, -C≡C-, -O-, ili -CR<5a>R<5b>-X-; Z represents -CH2-, -X-CR<5a>R<5b>-, -CR<5c>=CR<5d>-, -CR<5e>R<5g>-CR<5f>R<5h>-, -C≡C-, -O-, or -CR<5a>R<5b>-X-;

R<5a>, R<5b>, R<5c>, R<5d>, R<5e>, R<5f>, R<5g>i R<5h>svaki nezavisno predstavlja vodonik ili C1-4alkil; R<5a>, R<5b>, R<5c>, R<5d>, R<5e>, R<5f>, R<5g> and R<5h> each independently represents hydrogen or C1-4alkyl;

X predstavlja -O-, -S-, ili -NR<11>-; X represents -O-, -S-, or -NR<11>-;

R<11>predstavlja vodonik, C1-4alkil, ili C1-4alkil supstituisan jednim supstituentom izabranim iz grupe koju čine -OH, -O-C1-4alkil, R<12>, -NH2, -NH-C1-4alkil i -N(C1-4alkil)2; R<11> represents hydrogen, C1-4alkyl, or C1-4alkyl substituted with one substituent selected from the group consisting of -OH, -O-C1-4alkyl, R<12>, -NH2, -NH-C1-4alkyl and -N(C1-4alkyl)2;

R<12>predstavlja 4-, 5-, 6- ili 7-člani heterociklični prsten koji sadrži jedan atom azota i opciono jedan atom kiseonika, pri čemu je navedeni 4-, 5-, 6- ili 7-člani heterociklični prsten povezan sa ostatkom molekula preko atoma azota prstena; R<12>represents a 4-, 5-, 6- or 7-membered heterocyclic ring containing one nitrogen atom and optionally one oxygen atom, wherein said 4-, 5-, 6- or 7-membered heterocyclic ring is connected to the rest of the molecule via a nitrogen atom of the ring;

Ar predstavlja 10-člani biciklični aromatični sistem prstenova koji se sastoji od dva kondenzovana 6-člana prstena, Ar represents a 10-membered bicyclic aromatic ring system consisting of two fused 6-membered rings,

pri čemu je najmanje 1 atom ugljenika prstena B zamenjen atomom azota; wherein at least 1 carbon atom of ring B is replaced by a nitrogen atom;

pri čemu je opciono 1 dodatni atom ugljenika prstena A ili prstena B zamenjen atomom azota, pod uslovom da, kada atom azota zamenjuje jedan od dva kondenzovana atoma ugljenika, karbonilna grupa je prisutna u navedenom bicikličnom aromatičnom sistemu prstenova; wherein optionally 1 additional carbon atom of ring A or ring B is replaced by a nitrogen atom, provided that, when the nitrogen atom replaces one of the two fused carbon atoms, a carbonyl group is present in said bicyclic aromatic ring system;

Ar je opciono supstituisan sa jednim, dva, tri ili četiri supstituenta od kojih je svaki nezavisno izabran iz grupe koju čine halo, -OH, -NH2, -NH-C1-4alkil, -N(C1-4alkil)2, cijano, -CF3, -C(=O)-NH-C1-4alkil, -C(=O)-C1-4alkil, C1-4alkiloksi i C1-4alkil opciono supstituisan jednim -NR<10a>R<10b>; Ar is optionally substituted with one, two, three or four substituents each independently selected from the group consisting of halo, -OH, -NH2, -NH-C1-4alkyl, -N(C1-4alkyl)2, cyano, -CF3, -C(=O)-NH-C1-4alkyl, -C(=O)-C1-4alkyl, C1-4alkyloxy and C1-4alkyl optionally substituted with one -NR<10a>R<10b>;

R<10a>i R<10b>svaki nezavisno predstavlja vodonik ili C1-4alkil; R<10a> and R<10b> each independently represents hydrogen or C1-4alkyl;

Het predstavlja biciklični aromatični heterociklični sistem prstenova izabran iz grupe koju čine (a-1), (a-2) i (a-3); Het represents a bicyclic aromatic heterocyclic ring system selected from the group consisting of (a-1), (a-2) and (a-3);

R<3a>, R<3b>i R<3c>svaki nezavisno predstavlja vodonik, halo, -NR<7a>R<7b>, ili -O-C1-4alkil; R<3a>, R<3b> and R<3c> each independently represents hydrogen, halo, -NR<7a>R<7b>, or -O-C1-4alkyl;

R<7a>predstavlja vodonik; R<7a> represents hydrogen;

R<7b>predstavlja vodonik ili C1-4alkil; R<7b>represents hydrogen or C1-4alkyl;

R<4a>, R<4b>i R<4c>svaki nezavisno predstavlja vodonik, halo, -NR<8a>R<8b>, ili C1-4alkil; R<8a>i R<8b>svaki nezavisno predstavlja vodonik ili C1-4alkil; R<4a>, R<4b> and R<4c> each independently represents hydrogen, halo, -NR<8a>R<8b>, or C1-4alkyl; R<8a> and R<8b> each independently represents hydrogen or C1-4alkyl;

Q<1>predstavlja N ili CR<6a>; Q<1>represents N or CR<6a>;

Q<2>predstavlja N ili CR<6b>; Q<2>represents N or CR<6b>;

Q<3>predstavlja N ili CR<6c>; Q<3>represents N or CR<6c>;

Q<4>predstavlja N ili CR<6d>; Q<4>represents N or CR<6d>;

pod uslovom da najviše jedan od Q<3>i Q<4>predstavlja N; provided that at most one of Q<3> and Q<4> represents N;

R<6a>, R<6b>, R<6c>, R<6d>, R<6e>i R<6f>svaki nezavisno predstavlja vodonik, halogen, C1-4alkil, -NR<9a>R<9b>, ili C1-4alkil supstituisan sa jednim, dva ili tri halo atoma; R<6a>, R<6b>, R<6c>, R<6d>, R<6e> and R<6f> each independently represents hydrogen, halogen, C1-4alkyl, -NR<9a>R<9b>, or C1-4alkyl substituted with one, two or three halo atoms;

R<9a>i R<9b>svaki nezavisno predstavlja vodonik ili C1-4alkil; R<9a> and R<9b> each independently represents hydrogen or C1-4alkyl;

i njegovim farmaceutski prihvatljivim adicionim solima i solvatima. and pharmaceutically acceptable addition salts and solvates thereof.

[0090] U jednom otelotvorenju, predmetni pronalazak se bavi novim jedinjenjima formule (I), pri čemu [0090] In one embodiment, the present invention relates to novel compounds of formula (I), wherein

R<1>predstavlja vodonik ili -C(=O)-C1-4alkil; R<1> represents hydrogen or -C(=O)-C1-4alkyl;

R<2>predstavlja vodonik ili -C(=O)-C1-4alkil; R<2> represents hydrogen or -C(=O)-C1-4alkyl;

Y predstavlja -CH2- ili -CF2-; Y represents -CH2- or -CF2-;

Z predstavlja -CH2-, -X-CR<5a>R<5b>-, -CR<5c>=CR<5d>-, -CR<5e>R<5g>-CR<5f>R<5h>-, -C≡C-, -O-, ili -CR<5a>R<5b>-X-; Z represents -CH2-, -X-CR<5a>R<5b>-, -CR<5c>=CR<5d>-, -CR<5e>R<5g>-CR<5f>R<5h>-, -C≡C-, -O-, or -CR<5a>R<5b>-X-;

R<5a>, R<5b>, R<5c>, R<5d>, R<50>, R<5f>, R<5g>i R<5h>svaki nezavisno predstavlja vodonik ili C1-4alkil; R<5a>, R<5b>, R<5c>, R<5d>, R<50>, R<5f>, R<5g> and R<5h> each independently represents hydrogen or C1-4alkyl;

X predstavlja -O-, -S-, ili -NR<11>-; X represents -O-, -S-, or -NR<11>-;

R<11>predstavlja vodonik, C1-4alkil, ili C1-4alkil supstituisan jednim supstituentom izabranim iz grupe koju čine -OH, -O-C1-4alkil, R<12>, -NH2, -NH-C1-4alkil i -N(C1-4alkil)2; R<11> represents hydrogen, C1-4alkyl, or C1-4alkyl substituted with one substituent selected from the group consisting of -OH, -O-C1-4alkyl, R<12>, -NH2, -NH-C1-4alkyl and -N(C1-4alkyl)2;

R<12>predstavlja 4-, 5-, 6- ili 7-člani heterociklični prsten koji sadrži jedan atom azota i opciono jedan atom kiseonika, pri čemu je navedeni 4-, 5-, 6- ili 7-člani heterociklični prsten povezan sa ostatkom molekula preko atoma azota prstena; R<12>represents a 4-, 5-, 6- or 7-membered heterocyclic ring containing one nitrogen atom and optionally one oxygen atom, wherein said 4-, 5-, 6- or 7-membered heterocyclic ring is connected to the rest of the molecule via a nitrogen atom of the ring;

Ar predstavlja 10-člani biciklični aromatični sistem prstenova koji se sastoji od dva kondenzovana 6-člana prstena, Ar represents a 10-membered bicyclic aromatic ring system consisting of two fused 6-membered rings,

4 4

pri čemu je najmanje 1 atom ugljenika prstena B zamenjen atomom azota; wherein at least 1 carbon atom of ring B is replaced by a nitrogen atom;

pri čemu je opciono 1 dodatni atom ugljenika prstena A ili prstena B zamenjen atomom azota, pod uslovom da, kada atom azota zamenjuje jedan od dva kondenzovana atoma ugljenika, karbonilna grupa je prisutna u navedenom bicikličnom aromatičnom sistemu prstenova; wherein optionally 1 additional carbon atom of ring A or ring B is replaced by a nitrogen atom, provided that, when the nitrogen atom replaces one of the two fused carbon atoms, a carbonyl group is present in said bicyclic aromatic ring system;

Ar je opciono supstituisan sa jednim, dva, tri ili četiri supstituenta od kojih je svaki nezavisno izabran iz grupe koju čine halo, -OH, -NH2, -NH-C1-4alkil, -N(C1-4alkil)2, -NHR<10d>, -NR<10c>R<10d>, cijano, -CF3, -C(=O)-NH2, -C(=O)-NH-C1-4alkil, -C(=O)-C1-4alkil, C1-4alkiloksi, -C(=O)-O-C1-4alkil, C3-6cikloalkil, -O-C3-6cikloalkil, -NH-C3-6cikloalkil, -N(C3-6cikloalkil)2, C2-6alkenil, C1-4alkil supstituisan jednim C1-4alkiloksi i C1-4alkil opciono supstituisan jednim -NR<10a>R<10b>; Ar is optionally substituted with one, two, three or four substituents each independently selected from the group consisting of halo, -OH, -NH2, -NH-C1-4alkyl, -N(C1-4alkyl)2, -NHR<10d>, -NR<10c>R<10d>, cyano, -CF3, -C(=O)-NH2, -C(=O)-NH-C1-4alkyl, -C(=O)-C1-4alkyl, C1-4alkyloxy, -C(=O)-O-C1-4alkyl, C3-6cycloalkyl, -O-C3-6cycloalkyl, -NH-C3-6cycloalkyl, -N(C3-6cycloalkyl)2, C2-6alkenyl, C1-4alkyl substituted with one C1-4alkyloxy and C1-4alkyl optionally substituted with one -NR<10a>R<10b>;

R<10a>i R<10b>svaki nezavisno predstavlja vodonik ili C1-4alkil; R<10a> and R<10b> each independently represents hydrogen or C1-4alkyl;

R<10c>i R<10d>svaki nezavisno predstavlja C3-6cikloalkil; R<13>; R<14>; C3-6cikloalkil supstituisan sa jednim, dva ili tri supstituenta od kojih je svaki nezavisno izabran iz grupe koju čine halo, -OH i -O-C1-4alkil; C1-4alkil supstituisan sa jednim, dva ili tri supstituenta od kojih je svaki nezavisno izabran iz grupe koju čine halo, -OH i -O-C1-R<10c> and R<10d> each independently represents C3-6cycloalkyl; R<13>; R<14>; C3-6cycloalkyl substituted with one, two or three substituents each independently selected from the group consisting of halo, -OH and -O-C1-4alkyl; C1-4alkyl substituted with one, two or three substituents each independently selected from the group consisting of halo, -OH and -O-C1-

4alkil; ili C1-4alkil supstituisan jednim supstituentom izabranim iz grupe koju čine C3-4alkyl; or C1-4alkyl substituted with one substituent selected from the group consisting of C3-

6cikloalkil, R<13>i R<14>; 6cycloalkyl, R<13> and R<14>;

R<13>predstavlja 4- do 7-člani monociklični aromatični prsten koji sadrži jedan, dva ili tri heteroatoma, svaki nezavisno izabran od O, S, S(=O)pi N; ili 6- do 11-člani biciklični kondenzovani aromatični prsten koji sadrži jedan, dva ili tri heteroatoma, svaki nezavisno izabran od O, S, S(=O)pi N; R<13>represents a 4- to 7-membered monocyclic aromatic ring containing one, two or three heteroatoms, each independently selected from O, S, S(=O) and N; or a 6- to 11-membered bicyclic fused aromatic ring containing one, two or three heteroatoms, each independently selected from O, S, S(=O) and N;

navedeni 4- do 7-člani monociklični aromatični prsten ili 6- do 11-člani biciklični kondenzovani aromatični prsten je opciono supstituisan sa jednim ili dva supstituenta izabrana iz grupe koju čini C1-4alkil; said 4- to 7-membered monocyclic aromatic ring or 6- to 11-membered bicyclic fused aromatic ring is optionally substituted with one or two substituents selected from the group consisting of C1-4alkyl;

p predstavlja 1 ili 2; p represents 1 or 2;

R<14>predstavlja fenil opciono supstituisan sa jednim, dva ili tri supstituenta od kojih je svaki nezavisno izabran iz grupe koju čini halo; R<14>represents phenyl optionally substituted with one, two or three substituents each independently selected from the group consisting of halo;

Het predstavlja biciklični aromatični heterociklični sistem prstenova izabran iz grupe koju čini (a-1); Het represents a bicyclic aromatic heterocyclic ring system selected from the group consisting of (a-1);

R<3a>predstavlja vodonik, halo, -NR<7a>R<7b>, C1-4alkil, C2-4alkenil, C3-6cikloalkil, -OH, ili -O-C1-4alkil; R<3a>represents hydrogen, halo, -NR<7a>R<7b>, C1-4alkyl, C2-4alkenyl, C3-6cycloalkyl, -OH, or -O-C1-4alkyl;

R<7a>predstavlja vodonik; R<7a> represents hydrogen;

R<7b>predstavlja vodonik, C3-6cikloalkil, ili C1-4alkil; R<7b>represents hydrogen, C3-6cycloalkyl, or C1-4alkyl;

R<4a>predstavlja vodonik, halo, -NR<8a>R<8b>, ili C1-4alkil; R<4a> represents hydrogen, halo, -NR<8a>R<8b>, or C1-4alkyl;

R<8a>i R<8b>svaki nezavisno predstavlja vodonik ili C1-4alkil; R<8a> and R<8b> each independently represents hydrogen or C1-4alkyl;

Q<1>predstavlja N ili CR<6a>; Q<1>represents N or CR<6a>;

Q<2>predstavlja N ili CR<6b>; Q<2>represents N or CR<6b>;

naročito, Q<1>i Q<2>predstavljaju CH; in particular, Q<1> and Q<2> represent CH;

R<6a>i R<6b>svaki nezavisno predstavlja vodonik, halogen, C1-4alkil, -NR<9a>R<9b>, ili C1-4alkil supstituisan sa jednim, dva ili tri halo atoma; R<6a> and R<6b> each independently represents hydrogen, halogen, C1-4alkyl, -NR<9a>R<9b>, or C1-4alkyl substituted with one, two or three halo atoms;

R<9a>i R<9b>svaki nezavisno predstavlja vodonik ili C1-4alkil; R<9a> and R<9b> each independently represents hydrogen or C1-4alkyl;

4 4

i njegovim farmaceutski prihvatljivim adicionim solima i solvatima. and pharmaceutically acceptable addition salts and solvates thereof.

[0091] U jednom otelotvorenju, predmetni pronalazak se bavi novim jedinjenjima formule (I), pri čemu [0091] In one embodiment, the present invention relates to novel compounds of formula (I), wherein

R<1>predstavlja vodonik ili -C(=O)-C1-4alkil; R<1> represents hydrogen or -C(=O)-C1-4alkyl;

R<2>predstavlja vodonik ili -C(=O)-C1-4alkil; R<2> represents hydrogen or -C(=O)-C1-4alkyl;

Y predstavlja -CH2- ili -CF2-; Y represents -CH2- or -CF2-;

Z predstavlja -CH2-, -X-CR<5a>R<5b>-, -CR<5c>=CR<5d>-, -CR<5e>R<5g>-CR<5f>R<5h>-, -C≡C-, -O-, ili -CR<5a>R<5b>-X-; Z represents -CH2-, -X-CR<5a>R<5b>-, -CR<5c>=CR<5d>-, -CR<5e>R<5g>-CR<5f>R<5h>-, -C≡C-, -O-, or -CR<5a>R<5b>-X-;

R<5a>, R<5b>, R<5c>, R<5d>, R<50>, R<5f>, R<5g>i R<5h>svaki nezavisno predstavlja vodonik ili C1-4alkil; R<5a>, R<5b>, R<5c>, R<5d>, R<50>, R<5f>, R<5g> and R<5h> each independently represents hydrogen or C1-4alkyl;

X predstavlja -O-, -S-, ili -NR<11>-; X represents -O-, -S-, or -NR<11>-;

R<11>predstavlja vodonik, C1-4alkil, ili C1-4alkil supstituisan jednim supstituentom izabranim iz grupe koju čine -OH, -O-C1-4alkil, R<12>, -NH2, -NH-C1-4alkil i -N(C1-4alkil)2; R<11> represents hydrogen, C1-4alkyl, or C1-4alkyl substituted with one substituent selected from the group consisting of -OH, -O-C1-4alkyl, R<12>, -NH2, -NH-C1-4alkyl and -N(C1-4alkyl)2;

R<12>predstavlja 4-, 5-, 6- ili 7-člani heterociklični prsten koji sadrži jedan atom azota i opciono jedan atom kiseonika, pri čemu je navedeni 4-, 5-, 6- ili 7-člani heterociklični prsten povezan sa ostatkom molekula preko atoma azota prstena; R<12>represents a 4-, 5-, 6- or 7-membered heterocyclic ring containing one nitrogen atom and optionally one oxygen atom, wherein said 4-, 5-, 6- or 7-membered heterocyclic ring is connected to the rest of the molecule via a nitrogen atom of the ring;

Ar predstavlja 10-člani biciklični aromatični sistem prstenova koji se sastoji od dva kondenzovana 6-člana prstena, Ar represents a 10-membered bicyclic aromatic ring system consisting of two fused 6-membered rings,

pri čemu je najmanje 1 atom ugljenika prstena B zamenjen atomom azota; wherein at least 1 carbon atom of ring B is replaced by a nitrogen atom;

4 4

pri čemu je opciono 1 dodatni atom ugljenika prstena A ili prstena B zamenjen atomom azota, pod uslovom da, kada atom azota zamenjuje jedan od dva kondenzovana atoma ugljenika, karbonilna grupa je prisutna u navedenom bicikličnom aromatičnom sistemu prstenova; wherein optionally 1 additional carbon atom of ring A or ring B is replaced by a nitrogen atom, provided that, when the nitrogen atom replaces one of the two fused carbon atoms, a carbonyl group is present in said bicyclic aromatic ring system;

Ar je opciono supstituisan sa jednim, dva, tri ili četiri supstituenta od kojih je svaki nezavisno izabran iz grupe koju čine halo, -OH, -NH2, -NH-C1-4alkil, -N(C1-4alkil)2, cijano, -CF3, -C(=O)-NH-C1-4alkil, -C(=O)-C1-4alkil, C1-4alkiloksi i C1-4alkil opciono supstituisan jednim -NR<10a>R<10b>; Ar is optionally substituted with one, two, three or four substituents each independently selected from the group consisting of halo, -OH, -NH2, -NH-C1-4alkyl, -N(C1-4alkyl)2, cyano, -CF3, -C(=O)-NH-C1-4alkyl, -C(=O)-C1-4alkyl, C1-4alkyloxy and C1-4alkyl optionally substituted with one -NR<10a>R<10b>;

R<10a>i R<10b>svaki nezavisno predstavlja vodonik ili C1-4alkil; R<10a> and R<10b> each independently represents hydrogen or C1-4alkyl;

Het predstavlja biciklični aromatični heterociklični sistem prstenova izabran iz grupe koju čini (a-1); Het represents a bicyclic aromatic heterocyclic ring system selected from the group consisting of (a-1);

R<3a>predstavlja vodonik, halo, -NR<7a>R<7b>, ili -O-C1-4alkil; R<3a> represents hydrogen, halo, -NR<7a>R<7b>, or -O-C1-4alkyl;

R<7a>predstavlja vodonik; R<7a> represents hydrogen;

R<7b>predstavlja vodonik ili C1-4alkil; R<7b>represents hydrogen or C1-4alkyl;

R<4a>predstavlja vodonik, halo, -NR<8a>R<8b>, ili C1-4alkil; R<4a> represents hydrogen, halo, -NR<8a>R<8b>, or C1-4alkyl;

R<8a>i R<8b>svaki nezavisno predstavlja vodonik ili C1-4alkil; R<8a> and R<8b> each independently represents hydrogen or C1-4alkyl;

Q<1>predstavlja N ili CR<6a>; Q<1>represents N or CR<6a>;

Q<2>predstavlja N ili CR<6b>; Q<2>represents N or CR<6b>;

naročito, Q<1>i Q<2>predstavljaju CH; in particular, Q<1> and Q<2> represent CH;

R<6a>i R<6b>svaki nezavisno predstavlja vodonik, halogen, C1-4alkil, -NR<9a>R<9b>, ili C1-4alkil supstituisan sa jednim, dva ili tri halo atoma; R<6a> and R<6b> each independently represents hydrogen, halogen, C1-4alkyl, -NR<9a>R<9b>, or C1-4alkyl substituted with one, two or three halo atoms;

4 4

R<9a>i R<9b>svaki nezavisno predstavlja vodonik ili C1-4alkil; R<9a> and R<9b> each independently represents hydrogen or C1-4alkyl;

i njegovim farmaceutski prihvatljivim adicionim solima i solvatima. and pharmaceutically acceptable addition salts and solvates thereof.

[0092] U jednom otelotvorenju, predmetni pronalazak se bavi novim jedinjenjima formule (I), pri čemu [0092] In one embodiment, the present invention relates to novel compounds of formula (I), wherein

R<1>predstavlja vodonik ili -C(=O)-C1-4alkil; R<1> represents hydrogen or -C(=O)-C1-4alkyl;

R<2>predstavlja vodonik ili -C(=O)-C1-4alkil; R<2> represents hydrogen or -C(=O)-C1-4alkyl;

Y predstavlja -CH2-; Y represents -CH2-;

Z predstavlja -CH2-, -X-CR<5a>R<5b>-, -CR<5c>=CR<5d>-, -CR<5e>R<5g>-CR<5f>R<5h>-, -C≡C-, ili -CR<5a>R<5b>-X-; Z represents -CH2-, -X-CR<5a>R<5b>-, -CR<5c>=CR<5d>-, -CR<5e>R<5g>-CR<5f>R<5h>-, -C≡C-, or -CR<5a>R<5b>-X-;

R<5a>, R<5b>, R<5c>, R<5d>, R<50>, R<5f>, R<5g>i R<5h>svaki nezavisno predstavlja vodonik ili C1-4alkil; R<5a>, R<5b>, R<5c>, R<5d>, R<50>, R<5f>, R<5g> and R<5h> each independently represents hydrogen or C1-4alkyl;

X predstavlja -O-, -S-, ili -NR<11>-; X represents -O-, -S-, or -NR<11>-;

R<11>predstavlja vodonik ili C1-4alkil; R<11> represents hydrogen or C1-4alkyl;

Ar predstavlja 10-člani biciklični aromatični sistem prstenova koji se sastoji od dva kondenzovana 6-člana prstena, Ar represents a 10-membered bicyclic aromatic ring system consisting of two fused 6-membered rings,

pri čemu je najmanje 1 atom ugljenika prstena B zamenjen atomom azota; wherein at least 1 carbon atom of ring B is replaced by a nitrogen atom;

4 4

pri čemu je opciono 1 dodatni atom ugljenika prstena A ili prstena B zamenjen atomom azota, pod uslovom da, kada atom azota zamenjuje jedan od dva kondenzovana atoma ugljenika, karbonilna grupa je prisutna u navedenom bicikličnom aromatičnom sistemu prstenova; wherein optionally 1 additional carbon atom of ring A or ring B is replaced by a nitrogen atom, provided that, when the nitrogen atom replaces one of the two fused carbon atoms, a carbonyl group is present in said bicyclic aromatic ring system;

Ar je opciono supstituisan sa jednim, dva, tri ili četiri supstituenta od kojih je svaki nezavisno izabran iz grupe koju čine halo, -OH, -NH2, -NH-C1-4alkil, -N(C1-4alkil)2, -NHR<10d>, cijano, -CF3, -C(=O)-NH2, -C(=O)-NH-C1-4alkil, C1-4alkiloksi, -C(=O)-O-C1-Ar is optionally substituted with one, two, three or four substituents each independently selected from the group consisting of halo, -OH, -NH2, -NH-C1-4alkyl, -N(C1-4alkyl)2, -NHR<10d>, cyano, -CF3, -C(=O)-NH2, -C(=O)-NH-C1-4alkyl, C1-4alkyloxy, -C(=O)-O-C1-

4alkil, C3-6cikloalkil, C2-6alkenil, C1-4alkil supstituisan jednim C1-4alkiloksi i C1-4alkil opciono supstituisan jednim -NR<10a>R<10b>; 4alkyl, C3-6cycloalkyl, C2-6alkenyl, C1-4alkyl substituted with one C1-4alkyloxy and C1-4alkyl optionally substituted with one -NR<10a>R<10b>;

R<10a>i R<10b>predstavljaju C1-4alkil; R<10a> and R<10b> represent C1-4alkyl;

R<10d>predstavlja C3-6cikloalkil; R<14>; C1-4alkil supstituisan sa jednim, dva ili tri halo supstituenta; ili C1-4alkil supstituisan jednim supstituentom izabranim iz grupe koju čine C3-6cikloalkil i R<14>; R<10d> represents C3-6cycloalkyl; R<14>; C 1-4 alkyl substituted with one, two or three halo substituents; or C1-4alkyl substituted with one substituent selected from the group consisting of C3-6cycloalkyl and R<14>;

R<14>predstavlja fenil opciono supstituisan sa jednim, dva ili tri supstituenta od kojih je svaki nezavisno izabran iz grupe koju čini halo; R<14>represents phenyl optionally substituted with one, two or three substituents each independently selected from the group consisting of halo;

Het predstavlja biciklični aromatični heterociklični sistem prstenova izabran iz grupe koju čine (a-1), (a-2) i (a-4); Het represents a bicyclic aromatic heterocyclic ring system selected from the group consisting of (a-1), (a-2) and (a-4);

R<3a>, R<3b>, R<3c>i R<3d>svaki nezavisno predstavlja vodonik, halo, -NR<7a>R<7b>, C2-4alkenil, C3-R<3a>, R<3b>, R<3c> and R<3d> each independently represent hydrogen, halo, -NR<7a>R<7b>, C2-4alkenyl, C3-

6cikloalkil, -OH, ili -O-C1-4alkil; 6cycloalkyl, -OH, or -O-C1-4alkyl;

R<7a>predstavlja vodonik; R<7a> represents hydrogen;

R<7b>predstavlja vodonik, C3-6cikloalkil, ili C1-4alkil; R<7b>represents hydrogen, C3-6cycloalkyl, or C1-4alkyl;

R<4a>, R<4b>, R<4c>, R<4d>, R<4e>i R<4f>svaki nezavisno predstavlja, halo, -NR<8a>R<8b>, ili C1-4alkil; R<4a>, R<4b>, R<4c>, R<4d>, R<4e> and R<4f> each independently represents, halo, -NR<8a>R<8b>, or C1-4alkyl;

R<8a>i R<8b>svaki nezavisno predstavlja vodonik; R<8a> and R<8b> each independently represents hydrogen;

4 4

Q<1>predstavlja CR<6a>; Q<1>represents CR<6a>;

Q<2>predstavlja CR<6b>; Q<2>represents CR<6b>;

Q<8>predstavlja CR<6g>; Q<8>represents CR<6g>;

Q<9>predstavlja CR<6h>; Q<9>represents CR<6h>;

Q<5>predstavlja CR<3d>; Q<6>predstavlja N; i Q<7>predstavlja CR<4f>; ili Q<5> represents CR<3d>; Q<6>represents N; and Q<7>represents CR<4f>; or

Q<5>predstavlja CR<3d>; Q<6>predstavlja CR<4e>; i Q<7>predstavlja N; ili Q<5> represents CR<3d>; Q<6>represents CR<4e>; and Q<7>represents N; or

Q<5>predstavlja N; Q<6>predstavlja CR<4e>; i Q<7>predstavlja CR<4f>; ili Q<5>represents N; Q<6>represents CR<4e>; and Q<7>represents CR<4f>; or

Q<5>predstavlja N; Q<6>predstavlja CR<4e>; i Q<7>predstavlja N; Q<5>represents N; Q<6> represents CR<4e>; and Q<7>represents N;

R<6a>, R<6b>, R<6c>, R<6d>, R<6e>, R<6f,>R<6g>i R<6h>svaki nezavisno predstavlja vodonik, halogen, ili C1-4alkil; R<6a>, R<6b>, R<6c>, R<6d>, R<6e>, R<6f,>R<6g> and R<6h> each independently represents hydrogen, halogen, or C1-4alkyl;

i njegovim farmaceutski prihvatljivim adicionim solima i solvatima. and pharmaceutically acceptable addition salts and solvates thereof.

[0093] U jednom otelotvorenju, predmetni pronalazak se bavi novim jedinjenjima formule (I), pri čemu [0093] In one embodiment, the present invention relates to novel compounds of formula (I), wherein

R<1>predstavlja vodonik ili -C(=O)-C1-4alkil; R<1> represents hydrogen or -C(=O)-C1-4alkyl;

R<2>predstavlja vodonik ili -C(=O)-C1-4alkil; R<2> represents hydrogen or -C(=O)-C1-4alkyl;

Y predstavlja -CH2-; Y represents -CH2-;

Z predstavlja -CH2-, -X-CR<5a>R<5b->, -CR<5c>=CR<5d>-, -CR<5e>R<5g>-CR<5f>R<5h>-, -C≡C-, -O-, ili -CR<5a>R<5b>-X-; Z represents -CH2-, -X-CR<5a>R<5b->, -CR<5c>=CR<5d>-, -CR<5e>R<5g>-CR<5f>R<5h>-, -C≡C-, -O-, or -CR<5a>R<5b>-X-;

R<5a>, R<5b>, R<5c>, R<5d>, R<50>, R<5f>, R<5g>i R<5h>svaki nezavisno predstavlja vodonik ili C1-4alkil; X predstavlja -O-, -S-, ili -NR<11>-; R<5a>, R<5b>, R<5c>, R<5d>, R<50>, R<5f>, R<5g> and R<5h> each independently represents hydrogen or C1-4alkyl; X represents -O-, -S-, or -NR<11>-;

R<11>predstavlja vodonik ili C1-4alkil; R<11> represents hydrogen or C1-4alkyl;

Ar predstavlja 10-člani biciklični aromatični sistem prstenova koji se sastoji od dva kondenzovana 6-člana prstena, Ar represents a 10-membered bicyclic aromatic ring system consisting of two fused 6-membered rings,

pri čemu je najmanje 1 atom ugljenika prstena B zamenjen atomom azota; wherein at least 1 carbon atom of ring B is replaced by a nitrogen atom;

pri čemu je opciono 1 dodatni atom ugljenika prstena A ili prstena B zamenjen atomom azota, pod uslovom da, kada atom azota zamenjuje jedan od dva kondenzovana atoma ugljenika, karbonilna grupa je prisutna u navedenom bicikličnom aromatičnom sistemu prstenova; wherein optionally 1 additional carbon atom of ring A or ring B is replaced by a nitrogen atom, provided that, when the nitrogen atom replaces one of the two fused carbon atoms, a carbonyl group is present in said bicyclic aromatic ring system;

Ar je opciono supstituisan sa jednim, dva, tri ili četiri supstituenta od kojih je svaki nezavisno izabran iz grupe koju čine halo, -OH, -NH2, -NH-C1-4alkil, -N(C1-4alkil)2, cijano, -CF3, -C(=O)-NH-C1-4alkil, -C(=O)-C1-4alkil, C1-4alkiloksi i C1-4alkil opciono supstituisan jednim -NR<10a>R<10b>; Ar is optionally substituted with one, two, three or four substituents each independently selected from the group consisting of halo, -OH, -NH2, -NH-C1-4alkyl, -N(C1-4alkyl)2, cyano, -CF3, -C(=O)-NH-C1-4alkyl, -C(=O)-C1-4alkyl, C1-4alkyloxy and C1-4alkyl optionally substituted with one -NR<10a>R<10b>;

R<10a>i R<10b>svaki nezavisno predstavlja vodonik ili C1-4alkil; R<10a> and R<10b> each independently represents hydrogen or C1-4alkyl;

Het predstavlja biciklični aromatični heterociklični sistem prstenova izabran iz grupe koju čine (a-1), (a-2) i (a-3); Het represents a bicyclic aromatic heterocyclic ring system selected from the group consisting of (a-1), (a-2) and (a-3);

R<3a>, R<3b>i R<3c>svaki nezavisno predstavlja vodonik, halo, -NR<7a>R<7b>, ili -O-C1-4alkil; R<3a>, R<3b> and R<3c> each independently represents hydrogen, halo, -NR<7a>R<7b>, or -O-C1-4alkyl;

R<7a>predstavlja vodonik; R<7a> represents hydrogen;

1 1

R<7b>predstavlja vodonik ili C1-4alkil; R<7b>represents hydrogen or C1-4alkyl;

R<4a>, R<4b>i R<4c>svaki nezavisno predstavlja vodonik, halo, -NR<8a>R<8b>, ili C1-4alkil; R<8a>i R<8b>svaki nezavisno predstavlja vodonik ili C1-4alkil; R<4a>, R<4b> and R<4c> each independently represents hydrogen, halo, -NR<8a>R<8b>, or C1-4alkyl; R<8a> and R<8b> each independently represents hydrogen or C1-4alkyl;

Q<1>predstavlja CR<6a>; Q<1>represents CR<6a>;

Q<2>predstavlja CR<6b>; Q<2>represents CR<6b>;

Q<3>predstavlja CR<6c>; Q<3>represents CR<6c>;

Q<4>predstavlja CR<6d>; Q<4>represents CR<6d>;

R<6a>, R<6b>, R<6c>, R<6d>, R<6e>i R<6f>svaki nezavisno predstavlja vodonik, halogen, C1-4alkil, -NR<9a>R<9b>, ili C1-4alkil supstituisan sa jednim, dva ili tri halo atoma; R<6a>, R<6b>, R<6c>, R<6d>, R<6e> and R<6f> each independently represents hydrogen, halogen, C1-4alkyl, -NR<9a>R<9b>, or C1-4alkyl substituted with one, two or three halo atoms;

R<9a>i R<9b>svaki nezavisno predstavlja vodonik ili C1-4alkil; R<9a> and R<9b> each independently represents hydrogen or C1-4alkyl;

i njegovim farmaceutski prihvatljivim adicionim solima i solvatima. and pharmaceutically acceptable addition salts and solvates thereof.

U jednom otelotvorenju, predmetni pronalazak se bavi novim jedinjenjima formule (I), pri čemu In one embodiment, the present invention relates to novel compounds of formula (I), wherein

R<1>predstavlja vodonik ili -C(=O)-C1-4alkil; R<1> represents hydrogen or -C(=O)-C1-4alkyl;

R<2>predstavlja vodonik ili -C(=O)-C1-4alkil; R<2> represents hydrogen or -C(=O)-C1-4alkyl;

Y predstavlja -CH2-; Y represents -CH2-;

Z predstavlja -CH2-, -X-CR<5a>R<5b>-, -CR<5c>=CR<5d>-, -CR<5e>R<5g>-CR<5f>R<5h>-, -C≡C-, -O-, ili -CR<5a>R<5b>-X-; Z represents -CH2-, -X-CR<5a>R<5b>-, -CR<5c>=CR<5d>-, -CR<5e>R<5g>-CR<5f>R<5h>-, -C≡C-, -O-, or -CR<5a>R<5b>-X-;

R<5a>, R<5b>, R<5c>, R<5d>, R<50>, R<5f>, R<5g>i R<5h>svaki nezavisno predstavlja vodonik ili C1-4alkil; R<5a>, R<5b>, R<5c>, R<5d>, R<50>, R<5f>, R<5g> and R<5h> each independently represents hydrogen or C1-4alkyl;

2 2

X predstavlja -O-, -S-, ili -NR<11>-; X represents -O-, -S-, or -NR<11>-;

R<11>predstavlja vodonik ili C1-4alkil; R<11> represents hydrogen or C1-4alkyl;

Ar predstavlja 10-člani biciklični aromatični sistem prstenova koji se sastoji od dva kondenzovana 6-člana prstena, Ar represents a 10-membered bicyclic aromatic ring system consisting of two fused 6-membered rings,

pri čemu je najmanje 1 atom ugljenika prstena B zamenjen atomom azota; wherein at least 1 carbon atom of ring B is replaced by a nitrogen atom;

pri čemu je opciono 1 dodatni atom ugljenika prstena A ili prstena B zamenjen atomom azota, pod uslovom da, kada atom azota zamenjuje jedan od dva kondenzovana atoma ugljenika, karbonilna grupa je prisutna u navedenom bicikličnom aromatičnom sistemu prstenova; wherein optionally 1 additional carbon atom of ring A or ring B is replaced by a nitrogen atom, provided that, when the nitrogen atom replaces one of the two fused carbon atoms, a carbonyl group is present in said bicyclic aromatic ring system;

Ar je opciono supstituisan jednim supstituentom izabranim iz grupe koju čine halo, -OH, -NH2, -NH-C1-4alkil, -N(C1-4alkil)2, cijano, -CF3, -C(=O)-NH-C1-4alkil, - C(=O)-C1-4alkil, C1-4alkiloksi i C1-4alkil opciono supstituisan jednim - NR<10>aR<10b>., Ar is optionally substituted with one substituent selected from the group consisting of halo, -OH, -NH2, -NH-C1-4alkyl, -N(C1-4alkyl)2, cyano, -CF3, -C(=O)-NH-C1-4alkyl, -C(=O)-C1-4alkyl, C1-4alkyloxy and C1-4alkyl optionally substituted with one - NR<10>aR<10b>.,

R<10a>i R<10b>svaki nezavisno predstavlja vodonik ili C1-4alkil; R<10a> and R<10b> each independently represents hydrogen or C1-4alkyl;

Het predstavlja biciklični aromatični heterociklični sistem prstenova izabran iz grupe koju čine (a-1), (a-2) i (a-3); Het represents a bicyclic aromatic heterocyclic ring system selected from the group consisting of (a-1), (a-2) and (a-3);

R<3a>, R<3b>i R<3c>predstavlja -NR<7a>k<7b>; R<3a>, R<3b> and R<3c> represent -NR<7a>k<7b>;

R<7a>predstavlja vodonik; R<7a> represents hydrogen;

R<7b>predstavlja vodonik; R<7b>represents hydrogen;

R<4a>, R<4b>i R<4c>svaki nezavisno predstavlja vodonik, halo, -NR<8a>R<8b>, ili C1-4alkil; R<8a>i R<8b>svaki nezavisno predstavlja vodonik ili C1-4alkil; R<4a>, R<4b> and R<4c> each independently represents hydrogen, halo, -NR<8a>R<8b>, or C1-4alkyl; R<8a> and R<8b> each independently represents hydrogen or C1-4alkyl;

Q<1>predstavlja CR<6a>; Q<1>represents CR<6a>;

Q<2>predstavlja CR<6b>; Q<2>represents CR<6b>;

Q<3>predstavlja CR<6c>; Q<3>represents CR<6c>;

Q<4>predstavlja CR<6d>; Q<4>represents CR<6d>;

R<6a>, R<6b>, R<6c>, R<6d>, R<6e>i R<6f>svaki nezavisno predstavlja vodonik, halogen, C1-4alkil, -NR<9a>R<9b>, ili C1-4alkil supstituisan sa jednim, dva ili tri halo atoma; R<6a>, R<6b>, R<6c>, R<6d>, R<6e> and R<6f> each independently represents hydrogen, halogen, C1-4alkyl, -NR<9a>R<9b>, or C1-4alkyl substituted with one, two or three halo atoms;

R<9a>i R<9b>svaki nezavisno predstavlja vodonik ili C1-4alkil; R<9a> and R<9b> each independently represents hydrogen or C1-4alkyl;

i njegovim farmaceutski prihvatljivim adicionim solima i solvatima. and pharmaceutically acceptable addition salts and solvates thereof.

[0094] U jednom otelotvorenju, predmetni pronalazak se bavi novim jedinjenjima formule (I), pri čemu [0094] In one embodiment, the present invention relates to novel compounds of formula (I), wherein

R<1>predstavlja vodonik ili -C(=O)-C1-4alkil; R<1> represents hydrogen or -C(=O)-C1-4alkyl;

R<2>predstavlja vodonik ili -C(=O)-C1-4alkil; naročito, R<1>i R<2>predstavljaju vodonik; R<2> represents hydrogen or -C(=O)-C1-4alkyl; in particular, R<1> and R<2> represent hydrogen;

Y predstavlja -CH2-; Y represents -CH2-;

Z predstavlja -CH2-, -X-CR<5a>R<5b>-, -CR<5c>=CR<5d>-, -CR<5e>R<5g>-CR<5f>R<5h>-, -C≡C-, ili -CR<5a>R<5b>-X-; Z represents -CH2-, -X-CR<5a>R<5b>-, -CR<5c>=CR<5d>-, -CR<5e>R<5g>-CR<5f>R<5h>-, -C≡C-, or -CR<5a>R<5b>-X-;

R<5a>, R<5b>, R<5c>, R<5d>, R<50>, R<5f>, R<5g>i R<5h>svaki nezavisno predstavlja vodonik ili C1-4alkil; R<5a>, R<5b>, R<5c>, R<5d>, R<50>, R<5f>, R<5g> and R<5h> each independently represents hydrogen or C1-4alkyl;

X predstavlja -O-, -S-, ili -NR<11>-; X represents -O-, -S-, or -NR<11>-;

4 4

R<11>predstavlja vodonik ili C1-4alkil; R<11> represents hydrogen or C1-4alkyl;

Ar predstavlja 10-člani biciklični aromatični sistem prstenova koji se sastoji od dva kondenzovana 6-člana prstena, Ar represents a 10-membered bicyclic aromatic ring system consisting of two fused 6-membered rings,

pri čemu je najmanje 1 atom ugljenika prstena B zamenjen atomom azota; wherein at least 1 carbon atom of ring B is replaced by a nitrogen atom;

pri čemu je opciono 1 dodatni atom ugljenika prstena A ili prstena B zamenjen atomom azota, pod uslovom da, kada atom azota zamenjuje jedan od dva kondenzovana atoma ugljenika, karbonilna grupa je prisutna u navedenom bicikličnom aromatičnom sistemu prstenova; wherein optionally 1 additional carbon atom of ring A or ring B is replaced by a nitrogen atom, provided that, when the nitrogen atom replaces one of the two fused carbon atoms, a carbonyl group is present in said bicyclic aromatic ring system;

Ar je opciono supstituisan sa jednim, dva ili tri supstituenta od kojih je svaki nezavisno izabran iz grupe koju čine halo, -OH, -NH2, -NH-C1-4alkil, -N(C1-4alkil)2, cijano, -CF3, -C(=O)-NH-C1-4alkil, C1-4alkiloksi i C1-4alkil; Ar is optionally substituted with one, two or three substituents each independently selected from the group consisting of halo, -OH, -NH2, -NH-C1-4alkyl, -N(C1-4alkyl)2, cyano, -CF3, -C(=O)-NH-C1-4alkyl, C1-4alkyloxy and C1-4alkyl;

Het predstavlja biciklični aromatični heterociklični sistem prstenova izabran iz grupe koju čine (a-1) i (a-2); Het represents a bicyclic aromatic heterocyclic ring system selected from the group consisting of (a-1) and (a-2);

R<3a>i R<3c>svaki nezavisno predstavlja halo, -NR<7a>R<7b>, ili -O-C1-4alkil; R<3a> and R<3c> each independently represents halo, -NR<7a>R<7b>, or -O-C1-4alkyl;

R<7a>predstavlja vodonik; R<7a> represents hydrogen;

R<7b>predstavlja vodonik; R<7b>represents hydrogen;

R<4a>i R<4c>svaki nezavisno predstavlja vodonik, halo, ili C1-4alkil; R<4a> and R<4c> each independently represents hydrogen, halo, or C1-4alkyl;

Q<1>predstavlja CR<6a>; Q<1>represents CR<6a>;

Q<2>predstavlja CR<6b>; Q<2>represents CR<6b>;

R<6a>, R<6b>, R<6e>i R<6f>svaki nezavisno predstavlja vodonik, halogen, ili C1-4alkil; i njegovim farmaceutski prihvatljivim adicionim solima i solvatima. R<6a>, R<6b>, R<6e> and R<6f> each independently represents hydrogen, halogen, or C1-4alkyl; and pharmaceutically acceptable addition salts and solvates thereof.

[0095] U jednom otelotvorenju, predmetni pronalazak se bavi novim jedinjenjima formule (I), pri čemu [0095] In one embodiment, the present invention relates to novel compounds of formula (I), wherein

R<1>predstavlja vodonik ili -C(=O)-C1-4alkil; R<1> represents hydrogen or -C(=O)-C1-4alkyl;

R<2>predstavlja vodonik ili -C(=O)-C1-4alkil; naročito, R<1>i R<2>predstavljaju vodonik; R<2> represents hydrogen or -C(=O)-C1-4alkyl; in particular, R<1> and R<2> represent hydrogen;

Y predstavlja -CH2-; Y represents -CH2-;

Z predstavlja -CH2-, -X-CR<5a>R<5b>-, -CR<5c>=CR<5d>-, -CR<5e>R<5g>-CR<5f>R<5h>-, -C≡C-, ili -CR<5a>R<5b>-X-; Z represents -CH2-, -X-CR<5a>R<5b>-, -CR<5c>=CR<5d>-, -CR<5e>R<5g>-CR<5f>R<5h>-, -C≡C-, or -CR<5a>R<5b>-X-;

R<5a>, R<5b>, R<5c>, R<5d>, R<50>, R<5f>, R<5g>i R<5h>svaki nezavisno predstavlja vodonik ili C1-4alkil; R<5a>, R<5b>, R<5c>, R<5d>, R<50>, R<5f>, R<5g> and R<5h> each independently represents hydrogen or C1-4alkyl;

X predstavlja -O-, -S-, ili -NR<11>-; X represents -O-, -S-, or -NR<11>-;

R<11>predstavlja vodonik ili C1-4alkil; R<11> represents hydrogen or C1-4alkyl;

Ar predstavlja 10-člani biciklični aromatični sistem prstenova koji se sastoji od dva kondenzovana 6-člana prstena, Ar represents a 10-membered bicyclic aromatic ring system consisting of two fused 6-membered rings,

pri čemu je najmanje 1 atom ugljenika prstena B zamenjen atomom azota; pri čemu je opciono 1 dodatni atom ugljenika prstena A ili prstena B zamenjen atomom azota, pod uslovom da, kada atom azota zamenjuje jedan od dva kondenzovana atoma ugljenika, karbonil grupa je prisutna u navedenom bicikličnom aromatičnom sistemu prstenova; wherein at least 1 carbon atom of ring B is replaced by a nitrogen atom; wherein optionally 1 additional carbon atom of ring A or ring B is replaced by a nitrogen atom, provided that, when the nitrogen atom replaces one of the two fused carbon atoms, a carbonyl group is present in said bicyclic aromatic ring system;

Ar je opciono supstituisan sa jednim, dva ili tri supstituenta od kojih je svaki nezavisno izabran iz grupe koju čine halo, -OH, -NH2, -NH-C1-4alkil, -N(C1-4alkil)2, -NHR<10d>, cijano, -CF3, -C(=O)-NH-C1-4alkil, C1-4alkiloksi i C1-4alkil; Ar is optionally substituted with one, two or three substituents each independently selected from the group consisting of halo, -OH, -NH2, -NH-C1-4alkyl, -N(C1-4alkyl)2, -NHR<10d>, cyano, -CF3, -C(=O)-NH-C1-4alkyl, C1-4alkyloxy and C1-4alkyl;

R<10d>predstavlja C1-4alkil supstituisan sa jednim, dva ili tri halo supstituenta; ili C1-4alkil supstituisan jednim C3-6cikloalkil; R<10d>represents C1-4 alkyl substituted with one, two or three halo substituents; or C1-4alkyl substituted with one C3-6cycloalkyl;

Het predstavlja biciklični aromatični heterociklični sistem prstenova izabran iz grupe koju čine (a-1) i (a-2); Het represents a bicyclic aromatic heterocyclic ring system selected from the group consisting of (a-1) and (a-2);

R<3a>i R<3c>svaki nezavisno predstavlja vodonik, halo, -NR<7a>R<7b>, ili -O-C1-4alkil; R7a predstavlja vodonik; R<3a> and R<3c> each independently represents hydrogen, halo, -NR<7a>R<7b>, or -O-C1-4alkyl; R7a represents hydrogen;

R<7b>predstavlja vodonik ili C1-4alkil; R<7b>represents hydrogen or C1-4alkyl;

R<4a>i R<4c>svaki nezavisno predstavlja vodonik, halo, ili C1-4alkil; R<4a> and R<4c> each independently represents hydrogen, halo, or C1-4alkyl;

Q<1>predstavlja CR<6a>; Q<1>represents CR<6a>;

Q<2>predstavlja CR<6b>; Q<2>represents CR<6b>;

R<6a>, R<6b>, R<6e>i R<6f>svaki nezavisno predstavlja vodonik, halogen, ili C1-4alkil; i njegovim farmaceutski prihvatljivim adicionim solima i solvatima. R<6a>, R<6b>, R<6e> and R<6f> each independently represents hydrogen, halogen, or C1-4alkyl; and pharmaceutically acceptable addition salts and solvates thereof.

[0096] Još jedno otelotvorenje predmetnog pronalaska se odnosi na ova jedinjenja formule (I) i njihove farmaceutski prihvatljive adicione soli i solvate, ili bilo koju njihovu podgrupu pomenutu u bilo kom drugom otelotvorenju, za koja važi jedno ili više od sledećih ograničenja: Another embodiment of the present invention relates to these compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof mentioned in any other embodiment, for which one or more of the following limitations apply:

(i) R<1>i R<2>predstavljaju vodonik; (i) R<1> and R<2> represent hydrogen;

(ii) Y predstavlja -CH2-; (ii) Y represents -CH2-;

(iii) Z predstavlja -CH2-, -X-CR<5a>R<5b>-, -CR<5c>=CR5<d>- , -CR<5e>R<5g>-CR<5f>R<5h>-, - ili -CR<5a>R<5b>-X-; (iii) Z represents -CH2-, -X-CR<5a>R<5b>-, -CR<5c>=CR5<d>- , -CR<5e>R<5g>-CR<5f>R<5h>-, - or -CR<5a>R<5b>-X-;

(iv) R<5a>, R<5b>, R<5c>, R<5d>, R<5e>, R<5f>, R<5g>i R<5h>predstavljaju vodonik; (iv) R<5a>, R<5b>, R<5c>, R<5d>, R<5e>, R<5f>, R<5g> and R<5h> represent hydrogen;

(v) X predstavlja -O-; (v) X represents -O-;

(vi) R<11>predstavlja vodonik ili C1-4alkil; (vi) R<11> represents hydrogen or C1-4alkyl;

(vii) Ar je opciono supstituisan sa jednim, dva ili tri supstituenta, naročito jednim supstituentom, od kojih je svaki nezavisno izabran iz grupe koju čine halo, -OH, -NH2, -NH-C1-4alkil, -N(C1-4alkil)2, cijano, -CF3, -C(=O)-NH-C1-4alkil, C1-4alkiloksi i C1-4alkil; (vii) Ar is optionally substituted with one, two or three substituents, especially one substituent, each of which is independently selected from the group consisting of halo, -OH, -NH2, -NH-C1-4alkyl, -N(C1-4alkyl)2, cyano, -CF3, -C(=O)-NH-C1-4alkyl, C1-4alkyloxy and C1-4alkyl;

(viii) Het predstavlja biciklični aromatični heterociklični sistem prstenova izabran iz grupe koju čine (a-1) i (a-2); (viii) Het represents a bicyclic aromatic heterocyclic ring system selected from the group consisting of (a-1) and (a-2);

(ix) R<3a>i R<3c>svaki nezavisno predstavlja halo, -NR<7a>R<7b>, ili -O-C1-4alkil; (ix) R<3a> and R<3c> each independently represents halo, -NR<7a>R<7b>, or -O-C1-4alkyl;

(x) R<7a>i R<7b>predstavljaju vodonik; (x) R<7a>and R<7b>represent hydrogen;

(xi) R<4a>i R<4c>svaki nezavisno predstavlja vodonik, halo, ili C1-4alkil; (xi) R<4a> and R<4c> are each independently hydrogen, halo, or C1-4alkyl;

(xii) Q<1>predstavlja CR<6a>; (xii) Q<1>represents CR<6a>;

(xiii) Q<2>predstavlja CR<6b>; (xiii) Q<2>represents CR<6b>;

(xiv) R<6a>, R<6b>, R<6e>i R<6f>svaki nezavisno predstavlja vodonik, halogen, ili C1-4alkil. (xiv) R<6a>, R<6b>, R<6e> and R<6f> each independently represents hydrogen, halogen, or C1-4alkyl.

[0097] U jednom otelotvorenju, predmetni pronalazak se bavi novim jedinjenjima formule (I), pri čemu [0097] In one embodiment, the present invention relates to novel compounds of formula (I), wherein

R<1>predstavlja vodonik; R<1> represents hydrogen;

R<2>predstavlja vodonik; R<2> represents hydrogen;

Y predstavlja -CH2-; Y represents -CH2-;

Z predstavlja -X-CR<5a>R<5b>-, -CR<5e>R<5g>-CR<5f>R<5h>-, ili -CR<5a>R<5b>-X-; Z represents -X-CR<5a>R<5b>-, -CR<5e>R<5g>-CR<5f>R<5h>-, or -CR<5a>R<5b>-X-;

R<5a>, R<5b>, R<5e>, R<5f>, R<5g>i R<5h>predstavljaju vodonik; R<5a>, R<5b>, R<5e>, R<5f>, R<5g> and R<5h> represent hydrogen;

X predstavlja -O-; X represents -O-;

Ar predstavlja Ar represents

pri čemu je Ar opciono supstituisan na poziciji označenoj sa α, supstituentom izabranim iz grupe koju čine -NH2, -NH-C1-4alkil i -NHR<10d>; i pri čemu je Ar opciono supstituisan na poziciji označenoj sa β, supstituentom izabranim iz grupe koju čine halo i CF3; wherein Ar is optionally substituted at the position indicated by α, with a substituent selected from the group consisting of -NH2, -NH-C1-4alkyl and -NHR<10d>; and wherein Ar is optionally substituted at the position indicated by β with a substituent selected from the group consisting of halo and CF 3 ;

pod uslovom da je Ar supstituisan na najmanje jednoj od pozicija označenih sa α ili β; provided that Ar is substituted in at least one of the positions indicated by α or β;

R<10d>predstavlja C3-6cikloalkil; C1-4alkil supstituisan sa jednim, dva ili tri halo supstituenta; ili C1-4alkil supstituisan jednim C3-6cikloalkil supstituentom; R<10d> represents C3-6cycloalkyl; C 1-4 alkyl substituted with one, two or three halo substituents; or C1-4alkyl substituted with one C3-6cycloalkyl substituent;

Het predstavlja biciklični aromatični heterociklični sistem prstenova izabran iz grupe koju čine (a-1) i (a-4); Het represents a bicyclic aromatic heterocyclic ring system selected from the group consisting of (a-1) and (a-4);

R<3a>i R<3d>svaki nezavisno predstavlja vodonik, halo, -NR<7a>R<7b>, C1-4alkil, ili -O-C1-4alkil; R<3a> and R<3d> each independently represents hydrogen, halo, -NR<7a>R<7b>, C1-4alkyl, or -O-C1-4alkyl;

R<7a>predstavlja vodonik; R<7a> represents hydrogen;

R<7b>predstavlja vodonik ili C1-4alkil; R<7b>represents hydrogen or C1-4alkyl;

R<4a>, R<4d>i R<4f>svaki nezavisno predstavlja vodonik ili halo; R<4a>, R<4d> and R<4f> each independently represents hydrogen or halo;

Q<1>predstavlja CR<6a>; Q<1>represents CR<6a>;

Q<2>predstavlja CR<6b>; Q<2>represents CR<6b>;

Q<8>predstavlja CR<6g>; Q<8>represents CR<6g>;

Q<9>predstavlja CR<6h>; Q<9>represents CR<6h>;

Q<5>predstavlja CR<3d>; Q<6>predstavlja N; i Q<7>predstavlja CR<4f>; Q<5> represents CR<3d>; Q<6>represents N; and Q<7>represents CR<4f>;

R<6a>, R<6b>, R<6g>i R<6h>predstavljaju vodonik; R<6a>, R<6b>, R<6g> and R<6h> represent hydrogen;

i njegovim farmaceutski prihvatljivim adicionim solima i solvatima. and pharmaceutically acceptable addition salts and solvates thereof.

[0098] Još jedno otelotvorenje predmetnog pronalaska se odnosi na ova jedinjenja formule (I) i njihove farmaceutski prihvatljive adicione soli i solvate, ili bilo koju njihovu podgrupu pomenutu u bilo kom drugom otelotvorenju, za koja važi jedno ili više od sledećih ograničenja: Another embodiment of the present invention relates to these compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof mentioned in any other embodiment, for which one or more of the following limitations apply:

(i) R<1>i R<2>predstavljaju vodonik; (i) R<1> and R<2> represent hydrogen;

(ii) Y predstavlja -CH2-; (ii) Y represents -CH2-;

(iii) Z predstavlja -X-CR<5a>R<5b>-, -CR<5e>R<5g>-CR<5f>R<5h>-, ili -CR<5a>R<5b>-X-; (iii) Z represents -X-CR<5a>R<5b>-, -CR<5e>R<5g>-CR<5f>R<5h>-, or -CR<5a>R<5b>-X-;

(iv) R<5a>, R<5b>, R<5e>, R<5f>, R<5g>i R<5h>predstavljaju vodonik; (iv) R<5a>, R<5b>, R<5e>, R<5f>, R<5g> and R<5h> represent hydrogen;

(v) X predstavlja -O-; (v) X represents -O-;

(vi) Ar predstavlja (vi) Ar represents

pri čemu je Ar opciono supstituisan na poziciji označenoj sa α, supstituentom izabranim iz grupe koju čine -NH2, -NH-C1-4alkil i -NHR<10d>; i pri čemu je Ar opciono supstituisan na poziciji označenoj sa β, supstituentom izabranim iz grupe koju čine halo i CF3; wherein Ar is optionally substituted at the position indicated by α, with a substituent selected from the group consisting of -NH2, -NH-C1-4alkyl and -NHR<10d>; and wherein Ar is optionally substituted at the position indicated by β with a substituent selected from the group consisting of halo and CF 3 ;

pod uslovom da je Ar supstituisan na najmanje jednoj od pozicija označenih sa α ili β; provided that Ar is substituted in at least one of the positions indicated by α or β;

(vii) R<10d>predstavlja C3-6cikloalkil; C1-4alkil supstituisan sa jednim, dva ili tri halo supstituenta; ili C1-4alkil supstituisan jednim C3-6cikloalkil supstituentom; (vii) R<10d> represents C3-6cycloalkyl; C 1-4 alkyl substituted with one, two or three halo substituents; or C1-4alkyl substituted with one C3-6cycloalkyl substituent;

(viii) Het predstavlja biciklični aromatični heterociklični sistem prstenova izabran iz grupe koju čine (a-1) i (a-4); (viii) Het represents a bicyclic aromatic heterocyclic ring system selected from the group consisting of (a-1) and (a-4);

(ix) R<3a>i R<3d>svaki nezavisno predstavlja vodonik, halo, -NR<7a>R<7b>, C1-4alkil, ili -O-C1-4alkil; (ix) R<3a> and R<3d> each independently represents hydrogen, halo, -NR<7a>R<7b>, C1-4alkyl, or -O-C1-4alkyl;

(x) R<7a>predstavlja vodonik; (x) R<7a>represents hydrogen;

(xi) R<7b>predstavlja vodonik ili C1-4alkil; (xi) R<7b>represents hydrogen or C1-4alkyl;

(xii) R<4a>, R<4d>i R<4f>svaki nezavisno predstavlja vodonik ili halo; (xii) R<4a>, R<4d> and R<4f> each independently represents hydrogen or halo;

(xiii) Q<1>predstavlja CR<6a>; (xiii) Q<1>represents CR<6a>;

(xiv) Q<2>predstavlja CR<6b>; (xiv) Q<2>represents CR<6b>;

(xv) Q<8>predstavlja CR<6g>; (xv) Q<8>represents CR<6g>;

(xvi) Q<9>predstavlja CR<6h>; (xvi) Q<9>represents CR<6h>;

1 1

(xvii) Q<5>predstavlja CR<3d>; Q<6>predstavlja N; i Q<7>predstavlja CR<4f>; (xvii) Q<5>represents CR<3d>; Q<6>represents N; and Q<7>represents CR<4f>;

(xviii) R<6a>, R<6b>, R<6g>i R<6h>predstavljaju vodonik. (xviii) R<6a>, R<6b>, R<6g>and R<6h>represent hydrogen.

[0099] U jednom otelotvorenju, predmetni pronalazak se bavi novim jedinjenjima formule (I), pri čemu [0099] In one embodiment, the present invention relates to novel compounds of formula (I), wherein

R<1>predstavlja vodonik; R<1> represents hydrogen;

R<2>predstavlja vodonik; R<2> represents hydrogen;

Y predstavlja -CH2-; Y represents -CH2-;

Z predstavlja -X-CR<5a>R<5b>-, -CR<5e>R<5g>-CR<5f>R<5h>-, ili -CR<5a>R<5b>-X-; Z represents -X-CR<5a>R<5b>-, -CR<5e>R<5g>-CR<5f>R<5h>-, or -CR<5a>R<5b>-X-;

R<5a>, R<5b>, R<5e>, R<5f>, R<5g>i R<5h>predstavljaju vodonik; R<5a>, R<5b>, R<5e>, R<5f>, R<5g> and R<5h> represent hydrogen;

X predstavlja -O-; X represents -O-;

Ar predstavlja Ar represents

pri čemu je Ar opciono supstituisan na poziciji označenoj sa α, supstituentom izabranim iz grupe koju čine -NH2, -NH-C1-4alkil i -NHR<10d>; i pri čemu je Ar opciono supstituisan na poziciji označenoj sa β, supstituentom izabranim iz grupe koju čine halo i CF3; wherein Ar is optionally substituted at the position indicated by α, with a substituent selected from the group consisting of -NH2, -NH-C1-4alkyl and -NHR<10d>; and wherein Ar is optionally substituted at the position indicated by β with a substituent selected from the group consisting of halo and CF 3 ;

pod uslovom da je Ar supstituisan na najmanje jednoj od pozicija označenih sa α ili β; provided that Ar is substituted in at least one of the positions indicated by α or β;

R<10d>predstavlja C3-6cikloalkil; C1-4alkil supstituisan sa jednim, dva ili tri halo supstituenta; ili C1-4alkil supstituisan jednim C3-6cikloalkil supstituentom; R<10d> represents C3-6cycloalkyl; C 1-4 alkyl substituted with one, two or three halo substituents; or C1-4alkyl substituted with one C3-6cycloalkyl substituent;

2 2

Het predstavlja biciklični aromatični heterociklični sistem prstenova izabran iz grupe koju čini (a-1); Het represents a bicyclic aromatic heterocyclic ring system selected from the group consisting of (a-1);

R<3a>predstavlja vodonik, halo, -NR<7a>R<7b>, C1-4alkil, ili -O-C1-4alkil; R<3a>represents hydrogen, halo, -NR<7a>R<7b>, C1-4alkyl, or -O-C1-4alkyl;

R<7a>predstavlja vodonik; R<7a> represents hydrogen;

R<7b>predstavlja vodonik ili C1-4alkil; R<7b>represents hydrogen or C1-4alkyl;

R<4a>predstavlja vodonik ili halo; R<4a>represents hydrogen or halo;

Q<1>predstavlja CR<6a>; Q<1>represents CR<6a>;

Q<2>predstavlja CR<6b>; Q<2>represents CR<6b>;

R<6a>i R<6b>predstavljaju vodonik; R<6a> and R<6b> represent hydrogen;

i njegovim farmaceutski prihvatljivim adicionim solima i solvatima. and pharmaceutically acceptable addition salts and solvates thereof.

[0100] U jednom otelotvorenju, predmetni pronalazak se bavi novim jedinjenjima formule (I), pri čemu [0100] In one embodiment, the present invention relates to novel compounds of formula (I), wherein

R<1>predstavlja vodonik; R<1> represents hydrogen;

R<2>predstavlja vodonik; R<2> represents hydrogen;

Y predstavlja -CH2-; Y represents -CH2-;

Z predstavlja -X-CR<5a>R<5b>- ili -CR<5e>R<5g>-CR<5f>R<5h>-; Z represents -X-CR<5a>R<5b>- or -CR<5e>R<5g>-CR<5f>R<5h>-;

R<5a>, R<5b>, R<5e>, R<5f>, R<5g>i R<5h>predstavljaju vodonik; R<5a>, R<5b>, R<5e>, R<5f>, R<5g> and R<5h> represent hydrogen;

X predstavlja -O-; X represents -O-;

Ar predstavlja Ar represents

pri čemu je Ar opciono supstituisan na poziciji označenoj sa α, supstituentom izabranim iz grupe koju čine -NH2, -NH-C1-4alkil i -NHR<10d>; i pri čemu je Ar opciono supstituisan na poziciji označenoj sa β, supstituentom izabranim iz grupe koju čine halo i CF3; wherein Ar is optionally substituted at the position indicated by α, with a substituent selected from the group consisting of -NH2, -NH-C1-4alkyl and -NHR<10d>; and wherein Ar is optionally substituted at the position indicated by β with a substituent selected from the group consisting of halo and CF 3 ;

pod uslovom da je Ar supstituisan na najmanje jednoj od pozicija označenih sa α ili β; provided that Ar is substituted in at least one of the positions indicated by α or β;

R<10d>predstavlja C3-6cikloalkil; C1-4alkil supstituisan sa jednim, dva ili tri halo supstituenta; ili C1-4alkil supstituisan jednim C3-6cikloalkil supstituentom; R<10d> represents C3-6cycloalkyl; C 1-4 alkyl substituted with one, two or three halo substituents; or C1-4alkyl substituted with one C3-6cycloalkyl substituent;

Het predstavlja biciklični aromatični heterociklični sistem prstenova izabran iz grupe koju čini (a-1); Het represents a bicyclic aromatic heterocyclic ring system selected from the group consisting of (a-1);

R<3a>predstavlja vodonik, halo, -NR<7a>R<7b>, C1-4alkil, ili -O-C1-4alkil; R<7a>predstavlja vodonik; R<3a>represents hydrogen, halo, -NR<7a>R<7b>, C1-4alkyl, or -O-C1-4alkyl; R<7a>represents hydrogen;

R<7b>predstavlja vodonik ili C1-4alkil; R<7b>represents hydrogen or C1-4alkyl;

R<4a>predstavlja vodonik ili halo; R<4a>represents hydrogen or halo;

Q<1>predstavlja CR<6a>; Q<1>represents CR<6a>;

Q<2>predstavlja CR<6b>; Q<2>represents CR<6b>;

R<6a>i R<6b>predstavljaju vodonik; R<6a> and R<6b> represent hydrogen;

i njegovim farmaceutski prihvatljivim adicionim solima i solvatima. and pharmaceutically acceptable addition salts and solvates thereof.

4 4

[0101] U jednom otelotvorenju, predmetni pronalazak se bavi novim jedinjenjima formule (I), pri čemu [0101] In one embodiment, the present invention relates to novel compounds of formula (I), wherein

R<1>predstavlja vodonik; R<1> represents hydrogen;

R<2>predstavlja vodonik; R<2> represents hydrogen;

Y predstavlja -CH2-; Y represents -CH2-;

Z predstavlja -X-CR<5a>R<5b>-, -CR<5e>R<5g>-CR<5f>R<5h>-, ili -CR<5a>R<5b>-X-; Z represents -X-CR<5a>R<5b>-, -CR<5e>R<5g>-CR<5f>R<5h>-, or -CR<5a>R<5b>-X-;

R<5a>, R<5b>, R<5e>, R<5f>, R<5g>i R<5h>predstavljaju vodonik; R<5a>, R<5b>, R<5e>, R<5f>, R<5g> and R<5h> represent hydrogen;

X predstavlja -O-; X represents -O-;

Ar predstavlja Ar represents

pri čemu je Ar supstituisan na poziciji označenoj sa α, supstituentom izabranim iz grupe koju čine -NH2, -NH-C1-4alkil i -NHR<10d>; wherein Ar is substituted at the position indicated by α, with a substituent selected from the group consisting of -NH2, -NH-C1-4alkyl and -NHR<10d>;

R<10d>predstavlja C3-6cikloalkil; ili C1-4alkil supstituisan jednim supstituentom izabranim iz grupe koju čine C3-6cikloalkil i R<14>; R<10d> represents C3-6cycloalkyl; or C1-4alkyl substituted with one substituent selected from the group consisting of C3-6cycloalkyl and R<14>;

R<14>predstavlja fenil opciono supstituisan sa jednim, dva ili tri supstituenta od kojih je svaki nezavisno izabran iz grupe koju čini halo; R<14>represents phenyl optionally substituted with one, two or three substituents each independently selected from the group consisting of halo;

Het predstavlja biciklični aromatični heterociklični sistem prstenova (a-1); Het represents a bicyclic aromatic heterocyclic system of rings (a-1);

R<3a>predstavlja vodonik, halo, -NR<7a>R<7b>, ili C1-4alkil; R<3a> represents hydrogen, halo, -NR<7a>R<7b>, or C1-4alkyl;

R<7a>predstavlja vodonik; R<7a> represents hydrogen;

R<7b>predstavlja vodonik ili C1-4alkil; R<7b>represents hydrogen or C1-4alkyl;

R<4a>predstavlja vodonik; R<4a> represents hydrogen;

Q<1>predstavlja CR<6a>; Q<1>represents CR<6a>;

Q<2>predstavlja CR<6b>; Q<2>represents CR<6b>;

R<6a>i R<6b>predstavljaju vodonik; R<6a> and R<6b> represent hydrogen;

i njegovim farmaceutski prihvatljivim adicionim solima i solvatima. and pharmaceutically acceptable addition salts and solvates thereof.

[0102] U jednom otelotvorenju, predmetni pronalazak se bavi novim jedinjenjima formule (I), pri čemu [0102] In one embodiment, the present invention relates to novel compounds of formula (I), wherein

R<1>predstavlja vodonik; R<1> represents hydrogen;

R<2>predstavlja vodonik; R<2> represents hydrogen;

Y predstavlja -CH2-; Y represents -CH2-;

Z predstavlja -X-CR<5a>R<5b>-, -CR<5e>R<5g>-CR<5f>R<5h>-, ili -CR<5a>R<5b>-X-; Z represents -X-CR<5a>R<5b>-, -CR<5e>R<5g>-CR<5f>R<5h>-, or -CR<5a>R<5b>-X-;

R<5a>, R<5b>, R<5e>, R<5f>, R<5g>i R<5h>predstavljaju vodonik; R<5a>, R<5b>, R<5e>, R<5f>, R<5g> and R<5h> represent hydrogen;

X predstavlja -O-; X represents -O-;

Ar predstavlja Ar represents

pri čemu je Ar opciono supstituisan na poziciji označenoj sa α, sa -NH2; i pri čemu je Ar opciono supstituisan na poziciji označenoj sa β, supstituentom izabranim iz grupe koju čine halo i CF3; wherein Ar is optionally substituted at the position indicated by α, with -NH2; and wherein Ar is optionally substituted at the position indicated by β with a substituent selected from the group consisting of halo and CF 3 ;

Het predstavlja biciklični aromatični heterociklični sistem prstenova (a-1); Het represents a bicyclic aromatic heterocyclic system of rings (a-1);

R<3a>predstavlja vodonik, halo, -NR<7a>R<7b>, ili C1-4alkil; R<3a> represents hydrogen, halo, -NR<7a>R<7b>, or C1-4alkyl;

R<7a>predstavlja vodonik; R<7a> represents hydrogen;

R<7b>predstavlja vodonik ili C1-4alkil; R<7b>represents hydrogen or C1-4alkyl;

R<4a>predstavlja vodonik; R<4a> represents hydrogen;

Q<1>predstavlja CR<6a>; Q<1>represents CR<6a>;

Q<2>predstavlja CR<6b>; Q<2>represents CR<6b>;

R<6a>i R<6b>predstavljaju vodonik; R<6a> and R<6b> represent hydrogen;

i njegovim farmaceutski prihvatljivim adicionim solima i solvatima. and pharmaceutically acceptable addition salts and solvates thereof.

[0103] U jednom otelotvorenju, predmetni pronalazak se bavi novim jedinjenjima formule (I), pri čemu [0103] In one embodiment, the present invention relates to novel compounds of formula (I), wherein

R<1>predstavlja vodonik; R<1> represents hydrogen;

R<2>predstavlja vodonik; R<2> represents hydrogen;

Y predstavlja -CH2-; Y represents -CH2-;

Z predstavlja -X-CR<5a>R<5b>-, -CR<5e>R<5g>-CR<5f>R<5h>-, ili -CR<5a>R<5b>-X-; Z represents -X-CR<5a>R<5b>-, -CR<5e>R<5g>-CR<5f>R<5h>-, or -CR<5a>R<5b>-X-;

R<5a>, R<5b>, R<5e>, R<5f>, R<5g>i R<5h>predstavljaju vodonik; R<5a>, R<5b>, R<5e>, R<5f>, R<5g> and R<5h> represent hydrogen;

X predstavlja -O-; X represents -O-;

Ar predstavlja Ar represents

pri čemu je Ar supstituisan na poziciji označenoj sa α, sa -NH2; i wherein Ar is substituted at the position indicated by α, with -NH2; and

pri čemu je Ar supstituisan na poziciji označenoj sa β, supstituentom izabranim iz grupe koju čine halo i CF3; wherein Ar is substituted at the position indicated by β, with a substituent selected from the group consisting of halo and CF3;

Het predstavlja biciklični aromatični heterociklični sistem prstenova (a-1); Het represents a bicyclic aromatic heterocyclic system of rings (a-1);

R<3a>predstavlja vodonik, halo, -NR<7a>R<7b>, ili C1-4alkil; R<3a> represents hydrogen, halo, -NR<7a>R<7b>, or C1-4alkyl;

R<7a>predstavlja vodonik; R<7a> represents hydrogen;

R<7b>predstavlja vodonik ili C1-4alkil; R<7b>represents hydrogen or C1-4alkyl;

R<4a>predstavlja vodonik; R<4a> represents hydrogen;

Q<1>predstavlja CR<6a>; Q<1>represents CR<6a>;

Q<2>predstavlja CR<6b>; Q<2>represents CR<6b>;

R<6a>i R<6b>predstavljaju vodonik; R<6a> and R<6b> represent hydrogen;

i njegovim farmaceutski prihvatljivim adicionim solima i solvatima. and pharmaceutically acceptable addition salts and solvates thereof.

[0104] U jednom otelotvorenju, predmetni pronalazak se bavi novim jedinjenjima formule (I), pri čemu [0104] In one embodiment, the present invention relates to novel compounds of formula (I), wherein

R<1>predstavlja vodonik; R<1> represents hydrogen;

R<2>predstavlja vodonik; R<2> represents hydrogen;

Y predstavlja -CH2-; Y represents -CH2-;

Z predstavlja -X-CR<5a>R<5b>-, -CR<5e>R<5g>-CR<5f>R<5h>-, ili -CR<5a>R<5b>-X-; Z represents -X-CR<5a>R<5b>-, -CR<5e>R<5g>-CR<5f>R<5h>-, or -CR<5a>R<5b>-X-;

R<5a>, R<5b>, R<5e>, R<5f>, R<5g>i R<5h>predstavljaju vodonik; R<5a>, R<5b>, R<5e>, R<5f>, R<5g> and R<5h> represent hydrogen;

X predstavlja -O-; Ar predstavlja X represents -O-; Ar represents

Het predstavlja biciklični aromatični heterociklični sistem prstenova (a-1); Het represents a bicyclic aromatic heterocyclic system of rings (a-1);

R<3a>predstavlja vodonik, halo, -NR<7a>R<7b>, ili C1-4alkil; R<3a> represents hydrogen, halo, -NR<7a>R<7b>, or C1-4alkyl;

R<7a>predstavlja vodonik; R<7a> represents hydrogen;

R<7b>predstavlja vodonik ili C1-4alkil; R<7b>represents hydrogen or C1-4alkyl;

R<4a>predstavlja vodonik; R<4a> represents hydrogen;

Q<1>predstavlja CR<6a>; Q<1>represents CR<6a>;

Q<2>predstavlja CR<6b>; Q<2>represents CR<6b>;

R<6a>i R<6b>predstavljaju vodonik; R<6a> and R<6b> represent hydrogen;

i njegovim farmaceutski prihvatljivim adicionim solima i solvatima. and pharmaceutically acceptable addition salts and solvates thereof.

[0105] U jednom otelotvorenju, predmetni pronalazak se bavi novim jedinjenjima formule (I), pri čemu [0105] In one embodiment, the present invention relates to novel compounds of formula (I), wherein

R<1>predstavlja vodonik ili -C(=O)-C1-4alkil; R<1> represents hydrogen or -C(=O)-C1-4alkyl;

R<2>predstavlja vodonik ili -C(=O)-C1-4alkil; R<2> represents hydrogen or -C(=O)-C1-4alkyl;

naročito, R<1>i R<2>predstavljaju vodonik; in particular, R<1> and R<2> represent hydrogen;

Y predstavlja -CH2- ili -O-; Y represents -CH2- or -O-;

Z predstavlja -X-CR<5a>R<5b>- ili -CH2CH2-; Z represents -X-CR<5a>R<5b>- or -CH2CH2-;

R<5a>i R<5b>svaki nezavisno predstavlja vodonik ili C1-4alkil; R<5a> and R<5b> each independently represents hydrogen or C1-4alkyl;

X predstavlja -O-, -S-, ili -NR<11>-; X represents -O-, -S-, or -NR<11>-;

R<11>predstavlja vodonik; R<11> represents hydrogen;

Ar predstavlja 10-člani biciklični aromatični sistem prstenova koji se sastoji od dva kondenzovana 6-člana prstena, Ar represents a 10-membered bicyclic aromatic ring system consisting of two fused 6-membered rings,

pri čemu je najmanje 1 atom ugljenika prstena B zamenjen atomom azota; wherein at least 1 carbon atom of ring B is replaced by a nitrogen atom;

pri čemu je opciono 1 dodatni atom ugljenika prstena A ili prstena B zamenjen atomom azota, pod uslovom da, kada atom azota zamenjuje jedan od dva kondenzovana atoma ugljenika, karbonil grupa je prisutna u navedenom bicikličnom aromatičnom sistemu prstenova; Ar je opciono supstituisan sa jednim ili dva supstituenta od kojih je svaki nezavisno izabran iz grupe koju čine halo, -OH, -NH2, -NH-C1-4alkil, -N(C1-4alkil)2, cijano, -CF3, -C(=O)-NH-C1-4alkil, -C(=O)-C1-4alkil, C1-4alkiloksi i C1-4alkil opciono supstituisan jednim -NR<10a>R<10b>; wherein optionally 1 additional carbon atom of ring A or ring B is replaced by a nitrogen atom, provided that, when the nitrogen atom replaces one of the two fused carbon atoms, a carbonyl group is present in said bicyclic aromatic ring system; Ar is optionally substituted with one or two substituents each independently selected from the group consisting of halo, -OH, -NH2, -NH-C1-4alkyl, -N(C1-4alkyl)2, cyano, -CF3, -C(=O)-NH-C1-4alkyl, -C(=O)-C1-4alkyl, C1-4alkyloxy and C1-4alkyl optionally substituted with one -NR<10a>R<10b>;

R<10a>i R<10b>svaki nezavisno predstavlja vodonik ili C1-4alkil; R<10a> and R<10b> each independently represents hydrogen or C1-4alkyl;

Het predstavlja biciklični aromatični heterociklični sistem prstenova izabran iz grupe koju čini (a-1); Het represents a bicyclic aromatic heterocyclic ring system selected from the group consisting of (a-1);

R<3a>predstavlja vodonik, halo, -NR<7a>R<7b>, ili -O-C1-4alkil; R<3a> represents hydrogen, halo, -NR<7a>R<7b>, or -O-C1-4alkyl;

R<7a>predstavlja vodonik; R<7a> represents hydrogen;

R<7b>predstavlja vodonik; R<7b>represents hydrogen;

R<4a>predstavlja vodonik, halo, -NR<8a>R<8b>, ili C1-4alkil; R<4a> represents hydrogen, halo, -NR<8a>R<8b>, or C1-4alkyl;

R<8a>i R<8b>svaki nezavisno predstavlja vodonik ili C1-4alkil; R<8a> and R<8b> each independently represents hydrogen or C1-4alkyl;

Q<1>predstavlja CR<6a>; Q<1>represents CR<6a>;

Q<2>predstavlja CR<6b>; Q<2>represents CR<6b>;

R<6a>i R<6b>svaki nezavisno predstavlja vodonik, halogen, C1-4alkil, -NR<9a>R<9b>, ili C1-4alkil supstituisan sa jednim, dva ili tri halo atoma; R<6a> and R<6b> each independently represents hydrogen, halogen, C1-4alkyl, -NR<9a>R<9b>, or C1-4alkyl substituted with one, two or three halo atoms;

R<9a>i R<9b>svaki nezavisno predstavlja vodonik ili C1-4alkil; R<9a> and R<9b> each independently represents hydrogen or C1-4alkyl;

i njegovim farmaceutski prihvatljivim adicionim solima i solvatima. and pharmaceutically acceptable addition salts and solvates thereof.

[0106] U jednom otelotvorenju, predmetni pronalazak se bavi novim jedinjenjima formule (I), pri čemu [0106] In one embodiment, the present invention relates to novel compounds of formula (I), wherein

1 1

R<1>predstavlja vodonik; R<1> represents hydrogen;

R<2>predstavlja vodonik; R<2> represents hydrogen;

Y predstavlja -CH2-; Y represents -CH2-;

Z predstavlja -CR<5e>R<5g>-CR<5f>R<5h>-; Z represents -CR<5e>R<5g>-CR<5f>R<5h>-;

R<5e>, R<5f>, R<5g>i R<5h>predstavljaju vodonik; R<5e>, R<5f>, R<5g> and R<5h> represent hydrogen;

Ar predstavlja bilo koji od sledećih 10-članih bicikličnih aromatičnih sistema prstenova: Ar represents any of the following 10-membered bicyclic aromatic ring systems:

Ar je opciono supstituisan sa jednim, dva, tri ili četiri supstituenta od kojih je svaki nezavisno izabran iz grupe koju čine halo, -NH2, -NH-C1-4alkil, -N(C1-4alkil)2, -NHR<10d>, -NR<10c>R<10d>; Ar is optionally substituted with one, two, three or four substituents each independently selected from the group consisting of halo, -NH2, -NH-C1-4alkyl, -N(C1-4alkyl)2, -NHR<10d>, -NR<10c>R<10d>;

R<10c>i R<10d>svaki nezavisno predstavlja C3-6cikloalkil; C3-6cikloalkil supstituisan sa jednim, dva ili tri supstituenta od kojih je svaki nezavisno izabran iz grupe koju čine halo, -OH i -O-C1-4alkil; C1-4alkil supstituisan sa jednim, dva ili tri supstituenta od kojih je svaki nezavisno izabran iz grupe koju čine halo, -OH i -O-C1-4alkil; ili C1-4alkil supstituisan jednim C3-6cikloalkil supstituentom; R<10c> and R<10d> each independently represents C3-6cycloalkyl; C3-6cycloalkyl substituted with one, two or three substituents each independently selected from the group consisting of halo, -OH and -O-C1-4alkyl; C1-4alkyl substituted with one, two or three substituents each independently selected from the group consisting of halo, -OH and -O-C1-4alkyl; or C1-4alkyl substituted with one C3-6cycloalkyl substituent;

Het predstavlja biciklični aromatični heterociklični sistem prstenova izabran iz grupe koju čini (a-1); Het represents a bicyclic aromatic heterocyclic ring system selected from the group consisting of (a-1);

R<3a>predstavlja vodonik, -NR<7a>R<7b>, ili -O-C1-4alkil; R<3a> represents hydrogen, -NR<7a>R<7b>, or -O-C1-4alkyl;

R<7a>predstavlja vodonik; R<7a> represents hydrogen;

2 2

R<7b>predstavlja vodonik ili C1-4alkil; R<7b>represents hydrogen or C1-4alkyl;

R<4a>predstavlja vodonik; R<4a> represents hydrogen;

Q<1>predstavlja CR<6a>; Q<1>represents CR<6a>;

Q<2>predstavlja CR<6b>; Q<2>represents CR<6b>;

R<6a>i R<6b>predstavljaju vodonik; R<6a> and R<6b> represent hydrogen;

i njegovim farmaceutski prihvatljivim adicionim solima i solvatima. and pharmaceutically acceptable addition salts and solvates thereof.

[0107] U jednom otelotvorenju, predmetni pronalazak se bavi novim jedinjenjima formule (I), pri čemu [0107] In one embodiment, the present invention relates to novel compounds of formula (I), wherein

R<1>predstavlja vodonik; R<1> represents hydrogen;

R<2>predstavlja vodonik; R<2> represents hydrogen;

Y predstavlja -CH2-; Y represents -CH2-;

Z predstavlja -CR<5e>R<5g>-CR<5f>R<5h>-; Z represents -CR<5e>R<5g>-CR<5f>R<5h>-;

R<5e>, R<5f>, R<5g>i R<5h>predstavljaju vodonik; R<5e>, R<5f>, R<5g> and R<5h> represent hydrogen;

Ar predstavlja Ar represents

Ar je opciono supstituisan sa jednim, dva, tri ili četiri supstituenta od kojih je svaki nezavisno izabran iz grupe koju čine halo, -NH2, -NH-C1-4alkil, -N(C1-4alkil)2, -NHR<10d>; R<10d>predstavlja C1-4alkil supstituisan sa jednim, dva ili tri halo supstituenta; ili C1-4alkil supstituisan jednim C3-6cikloalkil supstituentom; Ar is optionally substituted with one, two, three or four substituents each independently selected from the group consisting of halo, -NH2, -NH-C1-4alkyl, -N(C1-4alkyl)2, -NHR<10d>; R<10d>represents C1-4 alkyl substituted with one, two or three halo substituents; or C1-4alkyl substituted with one C3-6cycloalkyl substituent;

Het predstavlja biciklični aromatični heterociklični sistem prstenova izabran iz grupe koju čini (a-1); Het represents a bicyclic aromatic heterocyclic ring system selected from the group consisting of (a-1);

R<3a>predstavlja vodonik, -NR<7a>R<7b>, ili -O-C1-4alkil; R<3a> represents hydrogen, -NR<7a>R<7b>, or -O-C1-4alkyl;

R<7a>predstavlja vodonik; R<7a> represents hydrogen;

R<7b>predstavlja vodonik ili C1-4alkil; R<7b>represents hydrogen or C1-4alkyl;

R<4a>predstavlja vodonik; R<4a> represents hydrogen;

Q<1>predstavlja CR<6a>; Q<1>represents CR<6a>;

Q<2>predstavlja CR<6b>; Q<2>represents CR<6b>;

R<6a>i R<6b>predstavljaju vodonik; R<6a> and R<6b> represent hydrogen;

i njegovim farmaceutski prihvatljivim adicionim solima i solvatima. and pharmaceutically acceptable addition salts and solvates thereof.

[0108] Još jedno otelotvorenje predmetnog pronalaska se odnosi na ova jedinjenja formule (I) i njihove farmaceutski prihvatljive adicione soli i solvate, ili bilo koju njihovu podgrupu pomenutu u bilo kom drugom otelotvorenju, za koja važi jedno ili više od sledećih ograničenja: [0108] Another embodiment of the present invention relates to these compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof mentioned in any other embodiment, for which one or more of the following limitations apply:

(i) R<1>predstavlja vodonik; (i) R<1> represents hydrogen;

R<2>predstavlja vodonik; R<2> represents hydrogen;

(ii) Y predstavlja -CH2-; (ii) Y represents -CH2-;

(iii) Z predstavlja -CR<5e>R<5g>-CR<5f>R<5h>-; (iii) Z represents -CR<5e>R<5g>-CR<5f>R<5h>-;

4 4

(iv) R<5e>, R<5f>, R<5g>i R<5h>predstavljaju vodonik; (iv) R<5e>, R<5f>, R<5g>and R<5h>represent hydrogen;

(v) Ar predstavlja (v) Ar represents

Ar je opciono supstituisan sa jednim, dva, tri ili četiri supstituenta od kojih je svaki nezavisno izabran iz grupe koju čine halo, -NH2, -NH-C1-4alkil, -N(C1-4alkil)2, -NHR<10d>; Ar is optionally substituted with one, two, three or four substituents each independently selected from the group consisting of halo, -NH2, -NH-C1-4alkyl, -N(C1-4alkyl)2, -NHR<10d>;

(vi) R<10d>predstavlja C1-4alkil supstituisan sa jednim, dva ili tri halo supstituenta; ili C1-4alkil supstituisan jednim C3-6cikloalkil supstituentom; (vi) R<10d> represents C1-4alkyl substituted with one, two or three halo substituents; or C1-4alkyl substituted with one C3-6cycloalkyl substituent;

(vii) Het predstavlja biciklični aromatični heterociklični sistem prstenova izabran iz grupe koju čini (a-1); (vii) Het represents a bicyclic aromatic heterocyclic ring system selected from the group consisting of (a-1);

(viii) R<3a>predstavlja vodonik, -NR<7a>R<7b>, ili -O-C1-4alkil; (viii) R<3a>represents hydrogen, -NR<7a>R<7b>, or -O-C1-4alkyl;

(ix) R<7a>predstavlja vodonik; (ix) R<7a>represents hydrogen;

R<7b>predstavlja vodonik ili C1-4alkil; R<7b>represents hydrogen or C1-4alkyl;

(x) R<4a>predstavlja vodonik; (x) R<4a>represents hydrogen;

(xi) Q<1>predstavlja CR<6a>; (xi) Q<1>represents CR<6a>;

Q<2>predstavlja CR<6b>; Q<2>represents CR<6b>;

(xii) R<6a>i R<6b>predstavljaju vodonik. (xii) R<6a>and R<6b>represent hydrogen.

[0109] Još jedno otelotvorenje predmetnog pronalaska se odnosi na ova jedinjenja formule (I) i njihove farmaceutski prihvatljive adicione soli i solvate, ili bilo koju njihovu podgrupu pomenutu u bilo kom drugom otelotvorenju, za koja važi jedno ili više od sledećih ograničenja: (i) R<1>predstavlja vodonik ili -C(=O)-C1-4alkil; [0109] Another embodiment of the present invention relates to these compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof mentioned in any other embodiment, for which one or more of the following restrictions apply: (i) R<1> represents hydrogen or -C(=O)-C1-4alkyl;

R<2>predstavlja vodonik ili -C(=O)-C1-4alkil; R<2> represents hydrogen or -C(=O)-C1-4alkyl;

naročito, R<1>i R<2>predstavljaju vodonik; in particular, R<1> and R<2> represent hydrogen;

(ii) Y predstavlja -CH2- ili -O-; (ii) Y represents -CH2- or -O-;

(iii) Z predstavlja -X-CR<5a>R<5b>- ili -CH2CH2-; (iii) Z represents -X-CR<5a>R<5b>- or -CH2CH2-;

(iv) R<5a>i R<5b>svaki nezavisno predstavlja vodonik ili C1-4alkil; (iv) R<5a> and R<5b> each independently represents hydrogen or C1-4alkyl;

(v) X predstavlja -O-, -S-, ili -NR<11>-; (v) X represents -O-, -S-, or -NR<11>-;

(vi) R<11>predstavlja vodonik; (vi) R<11>represents hydrogen;

(vii) Ar je opciono supstituisan sa jednim ili dva supstituenta od kojih je svaki nezavisno izabran iz grupe koju čine halo, -OH, -NH2, -NH-C1-4alkil, -N(C1-4alkil)2, cijano, -CF3, -C(=O)-NH-C1-4alkil, -C(=O)-C1-4alkil, C1-4alkiloksi i C1-4alkil opciono supstituisan jednim -NR<10a>R<10b>; (vii) Ar is optionally substituted with one or two substituents each independently selected from the group consisting of halo, -OH, -NH2, -NH-C1-4alkyl, -N(C1-4alkyl)2, cyano, -CF3, -C(=O)-NH-C1-4alkyl, -C(=O)-C1-4alkyl, C1-4alkyloxy and C1-4alkyl optionally substituted with one -NR<10a>R<10b>;

(viii) R<10a>i R<10b>svaki nezavisno predstavlja vodonik ili C1-4alkil; (viii) R<10a> and R<10b> each independently represents hydrogen or C1-4alkyl;

(ix) Het predstavlja biciklični aromatični heterociklični sistem prstenova izabran iz grupe koju čini (a-1); (ix) Het represents a bicyclic aromatic heterocyclic ring system selected from the group consisting of (a-1);

(x) R<3a>predstavlja vodonik, halo, -NR<7a>R<7b>, ili -O-C1-4alkil; (x) R<3a>represents hydrogen, halo, -NR<7a>R<7b>, or -O-C1-4alkyl;

(xi) R<7a>predstavlja vodonik; (xi) R<7a>represents hydrogen;

R<7b>predstavlja vodonik; R<7b>represents hydrogen;

(xii) R<4a>predstavlja vodonik, halo, -NR<8a>R<8b>, ili C1-4alkil; (xii) R<4a>represents hydrogen, halo, -NR<8a>R<8b>, or C1-4alkyl;

(xiii) R<8a>i R<8b>svaki nezavisno predstavlja vodonik ili C1-4alkil; (xiii) R<8a> and R<8b> each independently represents hydrogen or C1-4alkyl;

(xiv) Q<1>predstavlja CR<6a>; (xiv) Q<1>represents CR<6a>;

(xv) Q<2>predstavlja CR<6b>; (xv) Q<2>represents CR<6b>;

(xvi) R<6a>i R<6b>svaki nezavisno predstavlja vodonik, halogen, C1-4alkil, -NR<9a>R<9b>, ili C1-4alkil supstituisan sa jednim, dva ili tri halo atoma; (xvi) R<6a> and R<6b> are each independently hydrogen, halogen, C1-4alkyl, -NR<9a>R<9b>, or C1-4alkyl substituted with one, two or three halo atoms;

(xvii) R<9a>i R<9b>svaki nezavisno predstavlja vodonik ili C1-4alkil. (xvii) R<9a> and R<9b> each independently represents hydrogen or C1-4alkyl.

[0110] U jednom otelotvorenju, predmetni pronalazak se bavi novim jedinjenjima formule (I), pri čemu [0110] In one embodiment, the present invention relates to novel compounds of formula (I), wherein

R<1>predstavlja vodonik ili -C(=O)-C1-4alkil; R<1> represents hydrogen or -C(=O)-C1-4alkyl;

R<2>predstavlja vodonik ili -C(=O)-C1-4alkil; R<2> represents hydrogen or -C(=O)-C1-4alkyl;

naročito, R<1>i R<2>predstavljaju vodonik; in particular, R<1> and R<2> represent hydrogen;

Y predstavlja -O-; Y represents -O-;

Z predstavlja -X-CR<5a>R<5b>-; Z represents -X-CR<5a>R<5b>-;

R<5a>i R<5b>svaki nezavisno predstavlja vodonik ili C1-4alkil; R<5a> and R<5b> each independently represents hydrogen or C1-4alkyl;

X predstavlja -O-, -S-, ili -NR<11>-; X represents -O-, -S-, or -NR<11>-;

R<11>predstavlja vodonik; R<11> represents hydrogen;

Ar predstavlja 10-člani biciklični aromatični sistem prstenova koji se sastoji od dva kondenzovana 6-člana prstena, Ar represents a 10-membered bicyclic aromatic ring system consisting of two fused 6-membered rings,

pri čemu je najmanje 1 atom ugljenika prstena B zamenjen atomom azota; wherein at least 1 carbon atom of ring B is replaced by a nitrogen atom;

pri čemu je opciono 1 dodatni atom ugljenika prstena A ili prstena B zamenjen atomom azota, pod uslovom da, kada atom azota zamenjuje jedan od dva kondenzovana atoma ugljenika, karbonil grupa je prisutna u navedenom bicikličnom aromatičnom sistemu prstenova; Ar je opciono supstituisan sa jednim ili dva supstituenta od kojih je svaki nezavisno izabran iz grupe koju čine halo, -OH, -NH2, -NH-C1-4alkil, -N(C1-4alkil)2, cijano, -CF3, -C(=O)-NH-C1-4alkil, -C(=O)-C1-4alkil, C1-4alkiloksi i C1-4alkil opciono supstituisan jednim -NR<10a>R<10b>; wherein optionally 1 additional carbon atom of ring A or ring B is replaced by a nitrogen atom, provided that, when the nitrogen atom replaces one of the two fused carbon atoms, a carbonyl group is present in said bicyclic aromatic ring system; Ar is optionally substituted with one or two substituents each independently selected from the group consisting of halo, -OH, -NH2, -NH-C1-4alkyl, -N(C1-4alkyl)2, cyano, -CF3, -C(=O)-NH-C1-4alkyl, -C(=O)-C1-4alkyl, C1-4alkyloxy and C1-4alkyl optionally substituted with one -NR<10a>R<10b>;

R<10a>i R<10b>svaki nezavisno predstavlja vodonik ili C1-4alkil; R<10a> and R<10b> each independently represents hydrogen or C1-4alkyl;

Het predstavlja biciklični aromatični heterociklični sistem prstenova izabran iz grupe koju čini (a-1); Het represents a bicyclic aromatic heterocyclic ring system selected from the group consisting of (a-1);

R<3a>predstavlja vodonik, halo, -NR<7a>R<7b>, ili -O-C1-4alkil; R<3a> represents hydrogen, halo, -NR<7a>R<7b>, or -O-C1-4alkyl;

R<7a>predstavlja vodonik; R<7a> represents hydrogen;

R<7b>predstavlja vodonik; R<7b>represents hydrogen;

R<4a>predstavlja vodonik, halo, -NR<8a>R<8b>, ili C1-4alkil; R<4a> represents hydrogen, halo, -NR<8a>R<8b>, or C1-4alkyl;

R<8a>i R<8b>svaki nezavisno predstavlja vodonik ili C1-4alkil; R<8a> and R<8b> each independently represents hydrogen or C1-4alkyl;

Q<1>predstavlja CR<6a>; Q<1>represents CR<6a>;

Q<2>predstavlja CR<6b>; Q<2>represents CR<6b>;

R<6a>i R<6b>svaki nezavisno predstavlja vodonik, halogen, C1-4alkil, -NR<9a>R<9b>, ili C1-4alkil supstituisan sa jednim, dva ili tri halo atoma; R<6a> and R<6b> each independently represents hydrogen, halogen, C1-4alkyl, -NR<9a>R<9b>, or C1-4alkyl substituted with one, two or three halo atoms;

R<9a>i R<9b>svaki nezavisno predstavlja vodonik ili C1-4alkil; R<9a> and R<9b> each independently represents hydrogen or C1-4alkyl;

i njegovim farmaceutski prihvatljivim adicionim solima i solvatima. and pharmaceutically acceptable addition salts and solvates thereof.

[0111] Još jedno otelotvorenje predmetnog pronalaska se odnosi na ova jedinjenja formule (I) i njihove farmaceutski prihvatljive adicione soli i solvate, ili bilo koju njihovu podgrupu pomenutu u bilo kom drugom otelotvorenju, za koja važi jedno ili više od sledećih ograničenja: Another embodiment of the present invention relates to these compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof mentioned in any other embodiment, for which one or more of the following limitations apply:

(i) R<1>predstavlja vodonik ili -C(=O)-C1-4alkil; (i) R<1> represents hydrogen or -C(=O)-C1-4alkyl;

R<2>predstavlja vodonik ili -C(=O)-C1-4alkil; R<2> represents hydrogen or -C(=O)-C1-4alkyl;

naročito, R<1>i R<2>predstavljaju vodonik; in particular, R<1> and R<2> represent hydrogen;

(ii) Y predstavlja -O-; (ii) Y represents -O-;

(iii) Z predstavlja -X-CR<5a>R<5b>-; (iii) Z represents -X-CR<5a>R<5b>-;

(iv) R<5a>i R<5b>svaki nezavisno predstavlja vodonik ili C1-4alkil; (iv) R<5a> and R<5b> each independently represents hydrogen or C1-4alkyl;

(v) X predstavlja -O-, -S-, ili -NR<11>-; (v) X represents -O-, -S-, or -NR<11>-;

(vi) R<11>predstavlja vodonik; (vi) R<11>represents hydrogen;

(vii) Ar je opciono supstituisan sa jednim ili dva supstituenta od kojih je svaki nezavisno izabran iz grupe koju čine halo, -OH, -NH2, -NH-C1-4alkil, -N(C1-4alkil)2, cijano, -CF3, -C(=O)-NH-C1-4alkil, -C(=O)-C1-4alkil, C1-4alkiloksi i C1-4alkil opciono supstituisan jednim -NR<10a>R<10b>; (vii) Ar is optionally substituted with one or two substituents each independently selected from the group consisting of halo, -OH, -NH2, -NH-C1-4alkyl, -N(C1-4alkyl)2, cyano, -CF3, -C(=O)-NH-C1-4alkyl, -C(=O)-C1-4alkyl, C1-4alkyloxy and C1-4alkyl optionally substituted with one -NR<10a>R<10b>;

(viii) R<10a>i R<10b>svaki nezavisno predstavlja vodonik ili C1-4alkil; (viii) R<10a> and R<10b> each independently represents hydrogen or C1-4alkyl;

(ix) Het predstavlja biciklični aromatični heterociklični sistem prstenova izabran iz grupe koju čini (a-1); (ix) Het represents a bicyclic aromatic heterocyclic ring system selected from the group consisting of (a-1);

(x) R<3a>predstavlja vodonik, halo, -NR<7a>R<7b>, ili -O-C1-4alkil; (x) R<3a>represents hydrogen, halo, -NR<7a>R<7b>, or -O-C1-4alkyl;

(xi) R<7a>predstavlja vodonik; (xi) R<7a>represents hydrogen;

R<7b>predstavlja vodonik; R<7b>represents hydrogen;

(xii) R<4a>predstavlja vodonik, halo, -NR<8a>R<8b>, ili C1-4alkil; (xii) R<4a>represents hydrogen, halo, -NR<8a>R<8b>, or C1-4alkyl;

(xiii) R<8a>i R<8b>svaki nezavisno predstavlja vodonik ili C1-4alkil; (xiii) R<8a> and R<8b> each independently represents hydrogen or C1-4alkyl;

(xiv) Q<1>predstavlja CR<6a>; (xiv) Q<1>represents CR<6a>;

(xv) Q<2>predstavlja CR<6b>; (xv) Q<2>represents CR<6b>;

(xvi) R<6a>i R<6b>svaki nezavisno predstavlja vodonik, halogen, C1-4alkil, -NR<9a>R<9b>, ili C1-4alkil supstituisan sa jednim, dva ili tri halo atoma; (xvi) R<6a> and R<6b> are each independently hydrogen, halogen, C1-4alkyl, -NR<9a>R<9b>, or C1-4alkyl substituted with one, two or three halo atoms;

(xvii) R<9a>i R<9b>svaki nezavisno predstavlja vodonik ili C1-4alkil. (xvii) R<9a> and R<9b> each independently represents hydrogen or C1-4alkyl.

[0112] U jednom otelotvorenju, predmetni pronalazak se bavi novim jedinjenjima formule (I), pri čemu [0112] In one embodiment, the present invention relates to novel compounds of formula (I), wherein

R<1>predstavlja vodonik ili -C(=O)-C1-4alkil; R<1> represents hydrogen or -C(=O)-C1-4alkyl;

R<2>predstavlja vodonik ili -C(=O)-C1-4alkil; R<2> represents hydrogen or -C(=O)-C1-4alkyl;

naročito, R<1>i R<2>predstavljaju vodonik; in particular, R<1> and R<2> represent hydrogen;

Y predstavlja -CH2- ili -O-; Y represents -CH2- or -O-;

Z predstavlja -X-CR<5a>R<5b>- ili -CH2CH2Z represents -X-CR<5a>R<5b>- or -CH2CH2

R<5a>i R<5b>svaki nezavisno predstavlja vodonik ili C1-4alkil; R<5a> and R<5b> each independently represents hydrogen or C1-4alkyl;

X predstavlja -O-, -S-, ili -NR<11>-; X represents -O-, -S-, or -NR<11>-;

R<11>predstavlja vodonik; R<11> represents hydrogen;

Ar predstavlja Ar represents

naročito, Ar predstavlja in particular, Ar represents

Ar je opciono supstituisan sa jednim ili dva supstituenta od kojih je svaki nezavisno izabran iz grupe koju čine halo, -OH, -NH2, -NH-C1-4alkil, -N(C1-4alkil)2, cijano, - CF3, -C(=O)-NH-C1-4alkil, -C(=O)-C1-4alkil, C1-4alkiloksi i C1-4alkil opciono supstituisan jednim -NR<10a>R<10b>; Ar is optionally substituted with one or two substituents each independently selected from the group consisting of halo, -OH, -NH2, -NH-C1-4alkyl, -N(C1-4alkyl)2, cyano, -CF3, -C(=O)-NH-C1-4alkyl, -C(=O)-C1-4alkyl, C1-4alkyloxy and C1-4alkyl optionally substituted with one -NR<10a>R<10b>;

R<10a>i R<10b>svaki nezavisno predstavlja vodonik ili C1-4alkil; R<10a> and R<10b> each independently represents hydrogen or C1-4alkyl;

Het predstavlja biciklični aromatični heterociklični sistem prstenova izabran iz grupe koju čini (a-1); Het represents a bicyclic aromatic heterocyclic ring system selected from the group consisting of (a-1);

R<3a>predstavlja vodonik, halo, -NR<7a>R<7b>, ili -O-C1-4alkil; R<3a> represents hydrogen, halo, -NR<7a>R<7b>, or -O-C1-4alkyl;

R<7a>predstavlja vodonik; R<7a> represents hydrogen;

R<7b>predstavlja vodonik; R<7b>represents hydrogen;

1 1

R<4a>predstavlja vodonik, halo, -NR<8a>R<8b>, ili C1-4alkil; R<4a> represents hydrogen, halo, -NR<8a>R<8b>, or C1-4alkyl;

R<8a>i R<8b>svaki nezavisno predstavlja vodonik ili C1-4alkil; R<8a> and R<8b> each independently represents hydrogen or C1-4alkyl;

Q<1>predstavlja CR<6a>; Q<1>represents CR<6a>;

Q<2>predstavlja CR<6b>; Q<2>represents CR<6b>;

R<6a>i R<6b>svaki nezavisno predstavlja vodonik, halogen, C1-4alkil, -NR<9a>R<9b>, ili C1-4alkil supstituisan sa jednim, dva ili tri halo atoma; R<6a> and R<6b> each independently represents hydrogen, halogen, C1-4alkyl, -NR<9a>R<9b>, or C1-4alkyl substituted with one, two or three halo atoms;

R<9a>i R<9b>svaki nezavisno predstavlja vodonik ili C1-4alkil; i njegovim farmaceutski prihvatljivim adicionim solima i solvatima. R<9a> and R<9b> each independently represents hydrogen or C1-4alkyl; and pharmaceutically acceptable addition salts and solvates thereof.

[0113] U jednom otelotvorenju, predmetni pronalazak se bavi novim jedinjenjima formule (I), pri čemu [0113] In one embodiment, the present invention relates to novel compounds of formula (I), wherein

R<1>predstavlja vodonik ili -C(=O)-C1-4alkil; R<1> represents hydrogen or -C(=O)-C1-4alkyl;

R<2>predstavlja vodonik ili -C(=O)-C1-4alkil; R<2> represents hydrogen or -C(=O)-C1-4alkyl;

naročito, R<1>i R<2>predstavljaju vodonik; in particular, R<1> and R<2> represent hydrogen;

Y predstavlja -O-; Y represents -O-;

Z predstavlja -X-CR<5a>R<5b>-; Z represents -X-CR<5a>R<5b>-;

R<5a>i R<5b>svaki nezavisno predstavlja vodonik ili C1-4alkil; R<5a> and R<5b> each independently represents hydrogen or C1-4alkyl;

X predstavlja -O-, -S-, ili -NR<11>-; X represents -O-, -S-, or -NR<11>-;

R<11>predstavlja vodonik; R<11> represents hydrogen;

2 2

Ar predstavlja Ar represents

naročito, Ar predstavlja in particular, Ar represents

Ar je opciono supstituisan sa jednim ili dva supstituenta od kojih je svaki nezavisno izabran iz grupe koju čine halo, -OH, -NH2, -NH-C1-4alkil, -N(C1-4alkil)2, cijano, - CF3, -C(=O)-NH-C1-4alkil, -C(=O)-C1-4alkil, C1-4alkiloksi i C1-4alkil opciono supstituisan jednim -NR<10a>R<10b>; Ar is optionally substituted with one or two substituents each independently selected from the group consisting of halo, -OH, -NH2, -NH-C1-4alkyl, -N(C1-4alkyl)2, cyano, -CF3, -C(=O)-NH-C1-4alkyl, -C(=O)-C1-4alkyl, C1-4alkyloxy and C1-4alkyl optionally substituted with one -NR<10a>R<10b>;

R<10a>i R<10b>svaki nezavisno predstavlja vodonik ili C1-4alkil; R<10a> and R<10b> each independently represents hydrogen or C1-4alkyl;

Het predstavlja biciklični aromatični heterociklični sistem prstenova izabran iz grupe koju čini (a-1); Het represents a bicyclic aromatic heterocyclic ring system selected from the group consisting of (a-1);

R<3a>predstavlja vodonik, halo, -NR<7a>R<7b>, ili -O-C1-4alkil; R<3a> represents hydrogen, halo, -NR<7a>R<7b>, or -O-C1-4alkyl;

R<7a>predstavlja vodonik; R<7a> represents hydrogen;

R<7b>predstavlja vodonik; R<7b>represents hydrogen;

R<4a>predstavlja vodonik, halo, -NR<8a>R<8b>, ili C1-4alkil; R<4a> represents hydrogen, halo, -NR<8a>R<8b>, or C1-4alkyl;

R<8a>i R<8b>svaki nezavisno predstavlja vodonik ili C1-4alkil; R<8a> and R<8b> each independently represents hydrogen or C1-4alkyl;

Q<1>predstavlja CR<6a>; Q<1>represents CR<6a>;

Q<2>predstavlja CR<6b>; Q<2>represents CR<6b>;

R<6a>i R<6b>svaki nezavisno predstavlja vodonik, halogen, C1-4alkil, -NR<9a>R<9b>, ili C1-4alkil supstituisan sa jednim, dva ili tri halo atoma; R<6a> and R<6b> each independently represents hydrogen, halogen, C1-4alkyl, -NR<9a>R<9b>, or C1-4alkyl substituted with one, two or three halo atoms;

R<9a>i R<9b>svaki nezavisno predstavlja vodonik ili C1-4alkil; R<9a> and R<9b> each independently represents hydrogen or C1-4alkyl;

i njegovim farmaceutski prihvatljivim adicionim solima i solvatima. and pharmaceutically acceptable addition salts and solvates thereof.

[0114] Još jedno otelotvorenje predmetnog pronalaska se odnosi na ova jedinjenja formule (I) i njihove farmaceutski prihvatljive adicione soli i solvate, ili bilo koju njihovu podgrupu pomenutu u bilo kom drugom otelotvorenju, za koja važi jedno ili više od sledećih ograničenja: [0114] Another embodiment of the present invention relates to these compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof mentioned in any other embodiment, for which one or more of the following limitations apply:

(i) R<1>predstavlja vodonik ili -C(=O)-C1-4alkil; (i) R<1> represents hydrogen or -C(=O)-C1-4alkyl;

R<2>predstavlja vodonik ili -C(=O)-C1-4alkil; R<2> represents hydrogen or -C(=O)-C1-4alkyl;

naročito, R<1>i R<2>predstavljaju vodonik; in particular, R<1> and R<2> represent hydrogen;

(ii) Y predstavlja -O-; (ii) Y represents -O-;

(iii) Z predstavlja -X-CR<5a>R<5b>-; (iii) Z represents -X-CR<5a>R<5b>-;

(iv) R<5a>i R<5b>svaki nezavisno predstavlja vodonik ili C1-4alkil; (iv) R<5a> and R<5b> each independently represents hydrogen or C1-4alkyl;

(v) X predstavlja -O-, -S-, ili -NR<11>-; (v) X represents -O-, -S-, or -NR<11>-;

(vi) R<11>predstavlja vodonik; (vi) R<11>represents hydrogen;

(vii) Ar predstavlja (vii) Ar represents

4 4

naročito, Ar predstavlja in particular, Ar represents

(viii) Ar je opciono supstituisan sa jednim ili dva supstituenta od kojih je svaki izabran iz grupe koju čine halo, -OH, -NH2, -NH-C1-4alkil, -N(C1-4alkil)2, cijano, -CF3, -C(=O)-NH-C1-4alkil, -C(=O)-C1-4alkil, C1-4alkiloksi i C1-4alkil opciono supstituisan jednim -NR<10a>R<10b>; (viii) Ar is optionally substituted with one or two substituents each selected from the group consisting of halo, -OH, -NH2, -NH-C1-4alkyl, -N(C1-4alkyl)2, cyano, -CF3, -C(=O)-NH-C1-4alkyl, -C(=O)-C1-4alkyl, C1-4alkyloxy and C1-4alkyl optionally substituted with one -NR<10a>R<10b>;

(ix) R<10a>i R<10b>svaki nezavisno predstavlja vodonik ili C1-4alkil; (ix) R<10a> and R<10b> each independently represents hydrogen or C1-4alkyl;

(x) Het predstavlja biciklični aromatični heterociklični sistem prstenova izabran iz grupe koju čini (a-1); (x) Het represents a bicyclic aromatic heterocyclic ring system selected from the group consisting of (a-1);

(xi) R<3a>predstavlja vodonik, halo, -NR<7a>R<7b>, ili -O-C1-4alkil; (xi) R<3a>represents hydrogen, halo, -NR<7a>R<7b>, or -O-C1-4alkyl;

(xii) R<7a>predstavlja vodonik; (xii) R<7a>represents hydrogen;

R<7b>predstavlja vodonik; R<7b>represents hydrogen;

(xiii) R<4a>predstavlja vodonik, halo, -NR<8a>R<8b>, ili C1-4alkil; (xiii) R<4a>represents hydrogen, halo, -NR<8a>R<8b>, or C1-4alkyl;

(xiv) R<8a>i R<8b>svaki nezavisno predstavlja vodonik ili C1-4alkil; (xiv) R<8a> and R<8b> each independently represents hydrogen or C1-4alkyl;

(xv) Q<1>predstavlja CR<6a>; (xv) Q<1>represents CR<6a>;

(xvi) Q<2>predstavlja CR<6b>; (xvi) Q<2>represents CR<6b>;

(xvii) R<6a>i R<6b>svaki nezavisno predstavlja vodonik, halogen, C1-4alkil, -NR<9a>R<9b>, ili C1-4alkil supstituisan sa jednim, dva ili tri halo atoma; (xvii) R<6a> and R<6b> each independently represents hydrogen, halogen, C1-4alkyl, -NR<9a>R<9b>, or C1-4alkyl substituted with one, two or three halo atoms;

(xviii) R<9a>i R<9b>svaki nezavisno predstavlja vodonik ili C1-4alkil. (xviii) R<9a> and R<9b> each independently represents hydrogen or C1-4alkyl.

[0115] U jednom otelotvorenju, predmetni pronalazak se bavi novim jedinjenjima formule (I), pri čemu [0115] In one embodiment, the present invention relates to novel compounds of formula (I), wherein

R<1>predstavlja vodonik ili -C(=O)-C1-4alkil; R<1> represents hydrogen or -C(=O)-C1-4alkyl;

R<2>predstavlja vodonik ili -C(=O)-C1-4alkil; R<2> represents hydrogen or -C(=O)-C1-4alkyl;

naročito, R<1>i R<2>predstavljaju vodonik; in particular, R<1> and R<2> represent hydrogen;

Y predstavlja -CH2-; Z predstavlja -X-CR<5a>R<5b>- ili -CH2CH2-; Y represents -CH2-; Z represents -X-CR<5a>R<5b>- or -CH2CH2-;

R<5a>i R<5b>predstavljaju vodonik; X predstavlja -O-; R<5a> and R<5b> represent hydrogen; X represents -O-;

R<11>predstavlja vodonik; R<11> represents hydrogen;

Ar predstavlja Ar represents

Ar je opciono supstituisan sa jednim ili dva supstituenta od kojih je svaki nezavisno izabran iz grupe koju čine halo, -OH, -NH2, -NH-C1-4alkil, -N(C1-4alkil)2, cijano i -CF3; Ar is optionally substituted with one or two substituents each independently selected from the group consisting of halo, -OH, -NH2, -NH-C1-4alkyl, -N(C1-4alkyl)2, cyano and -CF3;

Het predstavlja biciklični aromatični heterociklični sistem prstenova izabran iz grupe koju čini (a-1); Het represents a bicyclic aromatic heterocyclic ring system selected from the group consisting of (a-1);

R<3a>predstavlja -NR<7a>R<7b>; R<3a>represents -NR<7a>R<7b>;

R<7a>predstavlja vodonik; R<7a> represents hydrogen;

R<7b>predstavlja vodonik; R<7b>represents hydrogen;

R<4a>predstavlja vodonik; R<4a> represents hydrogen;

Q<1>predstavlja CR<6a>; Q<2>predstavlja CR<6b>; R<6a>i R<6b>predstavljaju vodonik; Q<1> represents CR<6a>; Q<2> represents CR<6b>; R<6a> and R<6b> represent hydrogen;

i njegovim farmaceutski prihvatljivim adicionim solima i solvatima. and pharmaceutically acceptable addition salts and solvates thereof.

[0116] U jednom otelotvorenju, predmetni pronalazak se bavi novim jedinjenjima formule (I), pri čemu [0116] In one embodiment, the present invention relates to novel compounds of formula (I), wherein

R<1>predstavlja vodonik ili -C(=O)-C1-4alkil; R<1> represents hydrogen or -C(=O)-C1-4alkyl;

R<2>predstavlja vodonik ili -C(=O)-C1-4alkil; R<2> represents hydrogen or -C(=O)-C1-4alkyl;

naročito, R<1>i R<2>predstavljaju vodonik; in particular, R<1> and R<2> represent hydrogen;

Y predstavlja -CH2-; Z predstavlja -X-CR<5a>R<5b>- ili -CH2CH2-; Y represents -CH2-; Z represents -X-CR<5a>R<5b>- or -CH2CH2-;

R<5a>i R<5b>predstavljaju vodonik; X predstavlja -O-; R<5a> and R<5b> represent hydrogen; X represents -O-;

R<11>predstavlja vodonik; R<11> represents hydrogen;

Ar predstavlja Ar represents

Ar je opciono supstituisan jednim supstituentom izabranim iz grupe koju čine halo, -OH, -NH2, -NH-C1-4alkil, -N(C1-4alkil)2, cijano i -CF3; Ar is optionally substituted with one substituent selected from the group consisting of halo, -OH, -NH2, -NH-C1-4alkyl, -N(C1-4alkyl)2, cyano and -CF3;

Het predstavlja biciklični aromatični heterociklični sistem prstenova izabran iz grupe koju čini (a-1); Het represents a bicyclic aromatic heterocyclic ring system selected from the group consisting of (a-1);

R<3a>predstavlja -NR<7a>R<7b>; R<3a>represents -NR<7a>R<7b>;

R<7a>predstavlja vodonik; R<7a> represents hydrogen;

R<7b>predstavlja vodonik; R<7b>represents hydrogen;

R<4a>predstavlja vodonik; R<4a> represents hydrogen;

Q<1>predstavlja CR<6a>; Q<2>predstavlja CR<6b>; R<6a>i R<6b>predstavljaju vodonik; Q<1> represents CR<6a>; Q<2> represents CR<6b>; R<6a> and R<6b> represent hydrogen;

i njegovim farmaceutski prihvatljivim adicionim solima i solvatima. and pharmaceutically acceptable addition salts and solvates thereof.

U jednom otelotvorenju, predmetni pronalazak se bavi novim jedinjenjima formule (I), pri čemu In one embodiment, the present invention relates to novel compounds of formula (I), wherein

R<1>predstavlja vodonik ili -C(=O)-C1-4alkil; R<1> represents hydrogen or -C(=O)-C1-4alkyl;

R<2>predstavlja vodonik ili -C(=O)-C1-4alkil; R<2> represents hydrogen or -C(=O)-C1-4alkyl;

naročito, R<1>i R<2>predstavljaju vodonik; in particular, R<1> and R<2> represent hydrogen;

Y predstavlja -O-; Z predstavlja -X-CR<5a>R<5b>-; Y represents -O-; Z represents -X-CR<5a>R<5b>-;

R<5a>i R<5b>predstavljaju vodonik; X predstavlja -O-; R<5a> and R<5b> represent hydrogen; X represents -O-;

R<11>predstavlja vodonik; R<11> represents hydrogen;

Ar predstavlja Ar represents

Ar je opciono supstituisan sa jednim ili dva supstituenta od kojih je svaki nezavisno izabran iz grupe koju čine halo, -OH, -NH2, -NH-C1-4alkil, -N(C1-4alkil)2, cijano i -CF3; Ar is optionally substituted with one or two substituents each independently selected from the group consisting of halo, -OH, -NH2, -NH-C1-4alkyl, -N(C1-4alkyl)2, cyano and -CF3;

Het predstavlja biciklični aromatični heterociklični sistem prstenova izabran iz grupe koju čini (a-1); Het represents a bicyclic aromatic heterocyclic ring system selected from the group consisting of (a-1);

R<3a>predstavlja -NR<7a>R<7b>; R<3a>represents -NR<7a>R<7b>;

R<7a>predstavlja vodonik; R<7a> represents hydrogen;

R<7b>predstavlja vodonik; R<7b>represents hydrogen;

R<4a>predstavlja vodonik; R<4a> represents hydrogen;

Q<1>predstavlja CR<6a>; Q<2>predstavlja CR<6b>; R<6a>i R<6b>predstavljaju vodonik; Q<1> represents CR<6a>; Q<2> represents CR<6b>; R<6a> and R<6b> represent hydrogen;

i njegovim farmaceutski prihvatljivim adicionim solima i solvatima. and pharmaceutically acceptable addition salts and solvates thereof.

[0117] U jednom otelotvorenju, predmetni pronalazak se bavi novim jedinjenjima formule (I), pri čemu [0117] In one embodiment, the present invention relates to novel compounds of formula (I), wherein

R<1>predstavlja vodonik ili -C(=O)-C1-4alkil; R<1> represents hydrogen or -C(=O)-C1-4alkyl;

R<2>predstavlja vodonik ili -C(=O)-C1-4alkil; R<2> represents hydrogen or -C(=O)-C1-4alkyl;

naročito, R<1>i R<2>predstavljaju vodonik; in particular, R<1> and R<2> represent hydrogen;

Y predstavlja -O-; Z predstavlja -X-CR<5a>R<5b>-; Y represents -O-; Z represents -X-CR<5a>R<5b>-;

R<5a>i R<5b>predstavljaju vodonik; X predstavlja -O-; R<5a> and R<5b> represent hydrogen; X represents -O-;

R<11>predstavlja vodonik; R<11> represents hydrogen;

Ar predstavlja Ar represents

Ar je opciono supstituisan jednim supstituentom izabranim iz grupe koju čine halo, -OH, -NH2, -NH-C1-4alkil, -N(C1-4alkil)2, cijano i -CF3; Ar is optionally substituted with one substituent selected from the group consisting of halo, -OH, -NH2, -NH-C1-4alkyl, -N(C1-4alkyl)2, cyano and -CF3;

Het predstavlja biciklični aromatični heterociklični sistem prstenova izabran iz grupe koju čini (a-1); Het represents a bicyclic aromatic heterocyclic ring system selected from the group consisting of (a-1);

R<3a>predstavlja -NR<7a>R<7b>; R<3a>represents -NR<7a>R<7b>;

R<7a>predstavlja vodonik; R<7a> represents hydrogen;

R<7b>predstavlja vodonik; R<7b>represents hydrogen;

R<4a>predstavlja vodonik; R<4a> represents hydrogen;

Q<1>predstavlja CR<6a>; Q<2>predstavlja CR<6b>; R<6a>i R<6b>predstavljaju vodonik; Q<1> represents CR<6a>; Q<2> represents CR<6b>; R<6a> and R<6b> represent hydrogen;

i njegovim farmaceutski prihvatljivim adicionim solima i solvatima. and pharmaceutically acceptable addition salts and solvates thereof.

[0118] U jednom otelotvorenju, predmetni pronalazak se bavi novim jedinjenjima formule (I), pri čemu [0118] In one embodiment, the present invention relates to novel compounds of formula (I), wherein

R<1>predstavlja vodonik ili -C(=O)-C1-4alkil; R<1> represents hydrogen or -C(=O)-C1-4alkyl;

R<2>predstavlja vodonik ili -C(=O)-C1-4alkil; R<2> represents hydrogen or -C(=O)-C1-4alkyl;

naročito, R<1>i R<2>predstavljaju vodonik; in particular, R<1> and R<2> represent hydrogen;

Y predstavlja -CH2-; Z predstavlja -X-CR<5a>R<5b>- ili -CH2CH2-; Y represents -CH2-; Z represents -X-CR<5a>R<5b>- or -CH2CH2-;

R<5a>i R<5b>predstavljaju vodonik; X predstavlja -O-; R<5a> and R<5b> represent hydrogen; X represents -O-;

R<11>predstavlja vodonik; R<11> represents hydrogen;

Ar predstavlja Ar represents

Het predstavlja biciklični aromatični heterociklični sistem prstenova izabran iz grupe koju čini (a-1); Het represents a bicyclic aromatic heterocyclic ring system selected from the group consisting of (a-1);

R<3a>predstavlja -NR<7a>R<7b>; R<3a>represents -NR<7a>R<7b>;

R<7a>predstavlja vodonik; R<7a> represents hydrogen;

R<7b>predstavlja vodonik; R<7b>represents hydrogen;

R<4a>predstavlja vodonik; R<4a> represents hydrogen;

Q<1>predstavlja CR<6a>; Q<2>predstavlja CR<6b>; R<6a>i R<6b>predstavljaju vodonik; Q<1> represents CR<6a>; Q<2> represents CR<6b>; R<6a> and R<6b> represent hydrogen;

i njegovim farmaceutski prihvatljivim adicionim solima i solvatima. and pharmaceutically acceptable addition salts and solvates thereof.

[0119] U jednom otelotvorenju, predmetni pronalazak se bavi novim jedinjenjima formule (I), pri čemu [0119] In one embodiment, the present invention relates to novel compounds of formula (I), wherein

R<1>predstavlja vodonik ili -C(=O)-C1-4alkil; R<1> represents hydrogen or -C(=O)-C1-4alkyl;

R<2>predstavlja vodonik ili -C(=O)-C1-4alkil; R<2> represents hydrogen or -C(=O)-C1-4alkyl;

naročito, R<1>i R<2>predstavljaju vodonik; in particular, R<1> and R<2> represent hydrogen;

1 1

Y predstavlja -O-; Z predstavlja -X-CR<5a>R<5b>-; Y represents -O-; Z represents -X-CR<5a>R<5b>-;

R<5a>i R<5b>predstavljaju vodonik; X predstavlja -O-; R<5a> and R<5b> represent hydrogen; X represents -O-;

R<11>predstavlja vodonik; R<11> represents hydrogen;

Ar predstavlja Ar represents

Het predstavlja biciklični aromatični heterociklični sistem prstenova izabran iz grupe koju čini (a-1); Het represents a bicyclic aromatic heterocyclic ring system selected from the group consisting of (a-1);

R<3a>predstavlja -NR<7a>R<7b>; R<3a>represents -NR<7a>R<7b>;

R<7a>predstavlja vodonik; R<7a> represents hydrogen;

R<7b>predstavlja vodonik; R<7b>represents hydrogen;

R<4a>predstavlja vodonik; R<4a> represents hydrogen;

Q<1>predstavlja CR<6a>; Q<2>predstavlja CR<6b>; R<6a>i R<6b>predstavljaju vodonik; Q<1> represents CR<6a>; Q<2> represents CR<6b>; R<6a> and R<6b> represent hydrogen;

i njegovim farmaceutski prihvatljivim adicionim solima i solvatima. and pharmaceutically acceptable addition salts and solvates thereof.

[0120] Još jedno otelotvorenje predmetnog pronalaska se odnosi na ova jedinjenja formule (I) i njihove farmaceutski prihvatljive adicione soli i solvate, ili bilo koju njihovu podgrupu pomenutu u bilo kom drugom otelotvorenju, za koja važi jedno ili više od sledećih ograničenja: [0120] Another embodiment of the present invention relates to these compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof mentioned in any other embodiment, for which one or more of the following limitations apply:

(i) R<1>predstavlja vodonik ili -C(=O)-C1-4alkil; (i) R<1> represents hydrogen or -C(=O)-C1-4alkyl;

R<2>predstavlja vodonik ili -C(=O)-C1-4alkil; R<2> represents hydrogen or -C(=O)-C1-4alkyl;

2 2

naročito, R<1>i R<2>predstavljaju vodonik; in particular, R<1> and R<2> represent hydrogen;

(ii) Y predstavlja -O-; (ii) Y represents -O-;

(iii) Z predstavlja -X-CR<5a>R<5b>-; (iii) Z represents -X-CR<5a>R<5b>-;

(iv) R<5a>i R<5b>predstavljaju vodonik; (iv) R<5a>and R<5b>represent hydrogen;

(v) X predstavlja -O-; (v) X represents -O-;

(vi) R<11>predstavlja vodonik; (vi) R<11>represents hydrogen;

(vii) Ar predstavlja (vii) Ar represents

Ar je opciono supstituisan sa jednim ili dva supstituenta od kojih je svaki nezavisno izabran iz grupe koju čine halo, -OH, -NH2, -NH-C1-4alkil, -N(C1-4alkil)2, cijano i -CF3; naročito, Ar je opciono supstituisan jednim supstituentom izabranim iz grupe koju čine halo, -OH, -NH2, -NH-C1-4alkil, -N(C1-4alkil)2, cijano i - CF3; konkretnije, Ar predstavlja Ar is optionally substituted with one or two substituents each independently selected from the group consisting of halo, -OH, -NH2, -NH-C1-4alkyl, -N(C1-4alkyl)2, cyano and -CF3; in particular, Ar is optionally substituted with one substituent selected from the group consisting of halo, -OH, -NH2, -NH-C1-4alkyl, -N(C1-4alkyl)2, cyano and -CF3; more specifically, Ar represents

redstavlja represents

(ix) Het predstavlja biciklični aromatični heterociklični sistem prstenova izabran iz grupe koju čini (a-1); (ix) Het represents a bicyclic aromatic heterocyclic ring system selected from the group consisting of (a-1);

(x) R<3a>predstavlja -NR<7a>R<7b>; (x) R<3a>represents -NR<7a>R<7b>;

(xi) R<7a>predstavlja vodonik; (xi) R<7a>represents hydrogen;

R<7b>predstavlja vodonik; R<7b>represents hydrogen;

(xii) R<4a>predstavlja vodonik; (xii) R<4a>represents hydrogen;

(xiii) Q<1>predstavlja CR<6a>; (xiii) Q<1>represents CR<6a>;

(xiv) Q<2>predstavlja CR<6b>; (xiv) Q<2>represents CR<6b>;

(xv) R<6a>i R<6b>predstavljaju vodonik. (xv) R<6a>and R<6b>represent hydrogen.

[0121] U jednom otelotvorenju, predmetni pronalazak se odnosi na ova jedinjenja formule (I) i njihove farmaceutski prihvatljive adicione soli i solvate, ili bilo koju njihovu podgrupu pomenutu u bilo kom drugom otelotvorenju, pri čemu R<1>i R<2>predstavljaju vodonik. [0121] In one embodiment, the present invention relates to these compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof mentioned in any other embodiment, wherein R<1> and R<2> represent hydrogen.

[0122] U jednom otelotvorenju, predmetni pronalazak se odnosi na ova jedinjenja formule (I) i njihove farmaceutski prihvatljive adicione soli i solvate, ili bilo koju njihovu podgrupu pomenutu u bilo kom drugom otelotvorenju, pri čemu R<1>predstavlja -C(=O)-C1-4alkil; R<2>predstavlja -C(=O)-C1-4alkil. [0122] In one embodiment, the present invention relates to these compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof mentioned in any other embodiment, wherein R<1> represents -C(=O)-C1-4alkyl; R<2> represents -C(=O)-C1-4alkyl.

[0123] U jednom otelotvorenju, predmetni pronalazak se odnosi na ova jedinjenja formule (I) i njihove farmaceutski prihvatljive adicione soli i solvate, ili bilo koju njihovu podgrupu pomenutu u bilo kom drugom otelotvorenju, pri čemu R<1>i R<2>predstavljaju vodonik; [0123] In one embodiment, the present invention relates to these compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof mentioned in any other embodiment, wherein R<1> and R<2> represent hydrogen;

Het predstavlja (a-1); Het represents (a-1);

Q<1>predstavlja CH; Q<2>predstavlja CH; i Q<1>represents CH; Q<2>represents CH; and

4 4

Ar predstavlja Ar represents

opciono supstituisan prema bilo kom od drugih otelotvorenja. optionally substituted according to any of the other embodiments.

[0124] U jednom otelotvorenju, predmetni pronalazak se odnosi na ova jedinjenja formule (I) i njihove farmaceutski prihvatljive adicione soli i solvate, ili bilo koju njihovu podgrupu pomenutu u bilo kom drugom otelotvorenju, pri čemu [0124] In one embodiment, the present invention relates to these compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof mentioned in any other embodiment, wherein

R<1>i R<2>predstavljaju vodonik; R<1> and R<2> represent hydrogen;

Het predstavlja (a-1); Het represents (a-1);

Q<1>predstavlja CH; Q<2>predstavlja CH; i Q<1>represents CH; Q<2>represents CH; and

Ar predstavlja Ar represents

pri čemu je Ar supstituisan sa jednim, dva, tri ili četiri supstituenta od kojih je svaki nezavisno izabran iz grupe koju čine halo, -NH2, -NH-C1-4alkil, -N(C1-4alkil)2, -NHR<10d>, -NR<10c>R<10d>; wherein Ar is substituted with one, two, three or four substituents each independently selected from the group consisting of halo, -NH2, -NH-C1-4alkyl, -N(C1-4alkyl)2, -NHR<10d>, -NR<10c>R<10d>;

R<10c>i R<10d>svaki nezavisno predstavlja C1-4alkil supstituisan sa jednim, dva ili tri halo supstituenta; ili C1-4alkil supstituisan jednim C3-6cikloalkil supstituentom. R<10c> and R<10d> each independently represents C1-4 alkyl substituted with one, two or three halo substituents; or C1-4alkyl substituted with one C3-6cycloalkyl substituent.

[0125] U jednom otelotvorenju, predmetni pronalazak se odnosi na ova jedinjenja formule (I) i njihove farmaceutski prihvatljive adicione soli i solvate, ili bilo koju njihovu podgrupu pomenutu u bilo kom drugom otelotvorenju, pri čemu Y predstavlja -O-. [0125] In one embodiment, the present invention relates to these compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof mentioned in any other embodiment, wherein Y represents -O-.

[0126] U jednom otelotvorenju, predmetni pronalazak se odnosi na ova jedinjenja formule (I) i njihove farmaceutski prihvatljive adicione soli i solvate, ili bilo koju njihovu podgrupu pomenutu u bilo kom drugom otelotvorenju, pri čemu Y predstavlja -CH2- ili -CF2-; naročito, pri čemu Y predstavlja -CH2-. [0126] In one embodiment, the present invention relates to these compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof mentioned in any other embodiment, wherein Y represents -CH2- or -CF2-; in particular, where Y represents -CH2-.

[0127] U jednom otelotvorenju, predmetni pronalazak se odnosi na ova jedinjenja formule (I) i njihove farmaceutski prihvatljive adicione soli i solvate, ili bilo koju njihovu podgrupu pomenutu u bilo kom drugom otelotvorenju, pri čemu najviše jedan od Q<1>i Q<2>predstavlja N. [0127] In one embodiment, the present invention relates to these compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates, or any of their subgroups mentioned in any other embodiment, wherein at most one of Q<1> and Q<2> represents N.

[0128] U jednom otelotvorenju, predmetni pronalazak se odnosi na ova jedinjenja formule (I) i njihove farmaceutski prihvatljive adicione soli i solvate, ili bilo koju njihovu podgrupu pomenutu u bilo kom drugom otelotvorenju, pri čemu Q<1>predstavlja CR<6a>; i Q<2>predstavlja CR<6b>; naročito, pri čemu Q<1>predstavlja CH; i Q<2>predstavlja CH. [0128] In one embodiment, the present invention relates to these compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof mentioned in any other embodiment, wherein Q<1>represents CR<6a>; and Q<2>represents CR<6b>; in particular, wherein Q<1>represents CH; and Q<2>represents CH.

[0129] U jednom otelotvorenju, predmetni pronalazak se odnosi na ova jedinjenja formule (I) i njihove farmaceutski prihvatljive adicione soli i solvate, ili bilo koju njihovu podgrupu pomenutu u bilo kom drugom otelotvorenju, pri čemu Het predstavlja (a-1); Q<1>predstavlja CR<6a>; i Q<2>predstavlja CR<6b>; naročito, pri čemu Q<1>predstavlja CH; i Q<2>predstavlja CH. [0129] In one embodiment, the present invention relates to these compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof mentioned in any other embodiment, wherein Het represents (a-1); Q<1> represents CR<6a>; and Q<2>represents CR<6b>; in particular, wherein Q<1>represents CH; and Q<2>represents CH.

[0130] U jednom otelotvorenju, predmetni pronalazak se odnosi na ova jedinjenja formule (I) i njihove farmaceutski prihvatljive adicione soli i solvate, ili bilo koju njihovu podgrupu pomenutu u bilo kom drugom otelotvorenju, pri čemu [0130] In one embodiment, the present invention relates to these compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof mentioned in any other embodiment, wherein

Q<5>predstavlja CR<3d>; Q<6>predstavlja N; i Q<7>predstavlja CR<4f>; ili Q<5> represents CR<3d>; Q<6>represents N; and Q<7>represents CR<4f>; or

Q<5>predstavlja CR<3d>; Q<6>predstavlja CR<4e>; i Q<7>predstavlja N; ili Q<5> represents CR<3d>; Q<6>represents CR<4e>; and Q<7>represents N; or

Q<5>predstavlja N; Q<6>predstavlja CR<4e>; i Q<7>predstavlja CR<4f>; ili Q<5>represents N; Q<6>represents CR<4e>; and Q<7>represents CR<4f>; or

Q<5>predstavlja N; Q<6>predstavlja CR<4e>; i Q<7>predstavlja N. Q<5>represents N; Q<6>represents CR<4e>; and Q<7>represents N.

[0131] U jednom otelotvorenju, predmetni pronalazak se odnosi na ova jedinjenja formule (I) i njihove farmaceutski prihvatljive adicione soli i solvate, ili bilo koju njihovu podgrupu pomenutu u bilo kom drugom otelotvorenju, pri čemu Het predstavlja biciklični aromatični heterociklični sistem prstenova izabran iz grupe koju čine (a-1), (a-2) i (a-4). [0131] In one embodiment, the present invention relates to these compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof mentioned in any other embodiment, wherein Het represents a bicyclic aromatic heterocyclic ring system selected from the group consisting of (a-1), (a-2) and (a-4).

[0132] U jednom otelotvorenju, predmetni pronalazak se odnosi na ova jedinjenja formule (I) i njihove farmaceutski prihvatljive adicione soli i solvate, ili bilo koju njihovu podgrupu pomenutu u bilo kom drugom otelotvorenju, pri čemu R<1>i R<2>predstavljaju vodonik; i Y predstavlja -O-. [0132] In one embodiment, the present invention relates to these compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof mentioned in any other embodiment, wherein R<1> and R<2> represent hydrogen; and Y represents -O-.

[0133] U jednom otelotvorenju, predmetni pronalazak se odnosi na ova jedinjenja formule (I) i njihove farmaceutski prihvatljive adicione soli i solvate, ili bilo koju njihovu podgrupu pomenutu u bilo kom drugom otelotvorenju, pri čemu Het predstavlja biciklični aromatični heterociklični sistem prstenova izabran iz grupe koju čine (a-1), (a-2) i (a-3). [0133] In one embodiment, the present invention relates to these compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof mentioned in any other embodiment, wherein Het represents a bicyclic aromatic heterocyclic ring system selected from the group consisting of (a-1), (a-2) and (a-3).

[0134] U jednom otelotvorenju, predmetni pronalazak se odnosi na ova jedinjenja formule (I) i njihove farmaceutski prihvatljive adicione soli i solvate, ili bilo koju njihovu podgrupu pomenutu u bilo kom drugom otelotvorenju, pri čemu Het predstavlja biciklični aromatični heterociklični sistem prstenova izabran iz grupe koju čine (a-1) i (a-2). [0134] In one embodiment, the present invention relates to these compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates, or any of their subgroups mentioned in any other embodiment, wherein Het represents a bicyclic aromatic heterocyclic ring system selected from the group consisting of (a-1) and (a-2).

[0135] U jednom otelotvorenju, predmetni pronalazak se odnosi na ova jedinjenja formule (I) i njihove farmaceutski prihvatljive adicione soli i solvate, ili bilo koju njihovu podgrupu pomenutu u bilo kom drugom otelotvorenju, pri čemu Het predstavlja biciklični aromatični heterociklični sistem prstenova izabran iz grupe koju čine (a-1) i (a-4). [0135] In one embodiment, the present invention relates to these compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates, or any of their subgroups mentioned in any other embodiment, wherein Het represents a bicyclic aromatic heterocyclic ring system selected from the group consisting of (a-1) and (a-4).

[0136] U jednom otelotvorenju, predmetni pronalazak se odnosi na ova jedinjenja formule (I) i njihove farmaceutski prihvatljive adicione soli i solvate, ili bilo koju njihovu podgrupu pomenutu u bilo kom drugom otelotvorenju, pri čemu Het predstavlja biciklični aromatični heterociklični sistem prstenova formule (a-1). [0136] In one embodiment, the present invention relates to these compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates, or any of their subgroups mentioned in any other embodiment, wherein Het represents a bicyclic aromatic heterocyclic ring system of formula (a-1).

[0137] U jednom otelotvorenju, predmetni pronalazak se odnosi na ova jedinjenja formule (I) i njihove farmaceutski prihvatljive adicione soli i solvate, ili bilo koju njihovu podgrupu pomenutu u bilo kom drugom otelotvorenju, pri čemu R<1>i R<2>predstavljaju vodonik; Y predstavlja -O-; i Het predstavlja biciklični aromatični heterociklični sistem prstenova formule (a-1). [0137] In one embodiment, the present invention relates to these compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof mentioned in any other embodiment, wherein R<1> and R<2> represent hydrogen; Y represents -O-; and Het represents a bicyclic aromatic heterocyclic ring system of formula (a-1).

[0138] U jednom otelotvorenju, predmetni pronalazak se odnosi na ova jedinjenja formule (I) i njihove farmaceutski prihvatljive adicione soli i solvate, ili bilo koju njihovu podgrupu pomenutu u bilo kom drugom otelotvorenju, pri čemu Ar predstavlja opciono supstituisani 10-člani biciklični aromatični sistem prstenova koji se sastoji od dva kondenzovana 6-člana prstena, [0138] In one embodiment, the present invention relates to these compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof mentioned in any other embodiment, wherein Ar represents an optionally substituted 10-membered bicyclic aromatic ring system consisting of two fused 6-membered rings,

pri čemu je najmanje 1 atom ugljenika prstena B zamenjen atomom azota; wherein at least 1 carbon atom of ring B is replaced by a nitrogen atom;

pri čemu je opciono 1 dodatni atom ugljenika prstena A ili prstena B zamenjen atomom azota, pod uslovom da atom azota ne zamenjuje jedan od dva kondenzovana atoma ugljenika. wherein optionally 1 additional ring A or ring B carbon atom is replaced by a nitrogen atom, provided that the nitrogen atom does not replace one of the two condensed carbon atoms.

[0139] U jednom otelotvorenju, predmetni pronalazak se odnosi na ova jedinjenja formule (I) i njihove farmaceutski prihvatljive adicione soli i solvate, ili bilo koju njihovu podgrupu pomenutu u bilo kom drugom otelotvorenju, pri čemu je Ar opciono supstituisan sa jednim ili dva supstituenta prema bilo kom drugom otelotvorenju. [0139] In one embodiment, the present invention relates to these compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof mentioned in any other embodiment, wherein Ar is optionally substituted with one or two substituents according to any other embodiment.

[0140] U jednom otelotvorenju, predmetni pronalazak se odnosi na ova jedinjenja formule (I) i njihove farmaceutski prihvatljive adicione soli i solvate, ili bilo koju njihovu podgrupu pomenutu u bilo kom drugom otelotvorenju, pri čemu je Ar opciono supstituisan jednim supstituentom prema bilo kom drugom otelotvorenju. [0140] In one embodiment, the present invention relates to these compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof mentioned in any other embodiment, wherein Ar is optionally substituted with one substituent according to any other embodiment.

[0141] U jednom otelotvorenju, predmetni pronalazak se odnosi na ova jedinjenja formule (I) i njihove farmaceutski prihvatljive adicione soli i solvate, ili bilo koju njihovu podgrupu pomenutu u bilo kom drugom otelotvorenju, pri čemu [0141] In one embodiment, the present invention relates to these compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof mentioned in any other embodiment, wherein

R<3a>, R<3c>, R<3b>predstavljaju vodonik; i R<3a>, R<3c>, R<3b>represent hydrogen; and

R<4a>, R<4c>, R<4b>predstavljaju vodonik, halo, ili C1-4alkil; naročito, R<4a>, R<4c>, R<4b>predstavljaju halo, ili C1-4alkil. R<4a>, R<4c>, R<4b> represent hydrogen, halo, or C1-4alkyl; in particular, R<4a>, R<4c>, R<4b> represent halo, or C1-4alkyl.

[0142] U jednom otelotvorenju, predmetni pronalazak se odnosi na ova jedinjenja formule (I) i njihove farmaceutski prihvatljive adicione soli i solvate, ili bilo koju njihovu podgrupu pomenutu u bilo kom drugom otelotvorenju, pri čemu [0142] In one embodiment, the present invention relates to these compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof mentioned in any other embodiment, wherein

R<3a>, R<3c>, R<3b>, R<3d>i R<3e>predstavljaju vodonik; i R<3a>, R<3c>, R<3b>, R<3d> and R<3e> represent hydrogen; and

R<4a>, R<4c>, R<4b>, R<4d>, R<4e>, R<4f>i R<4g>predstavljaju vodonik, halo, ili C1-4alkil; naročito R<4a>, R<4c>, R<4b>, R<4d>, R<4e>, R<4f> and R<4g> represent hydrogen, halo, or C1-4alkyl; especially

R<4a>, R<4c>, R<4b>, R<4d>, R<4e>, R<4f>i R<4g>predstavljaju halo, ili C1-4alkil. R<4a>, R<4c>, R<4b>, R<4d>, R<4e>, R<4f> and R<4g> represent halo, or C1-4alkyl.

[0143] U jednom otelotvorenju, predmetni pronalazak se odnosi na ova jedinjenja formule (I) i njihove farmaceutski prihvatljive adicione soli i solvate, ili bilo koju njihovu podgrupu pomenutu u bilo kom drugom otelotvorenju, pri čemu [0143] In one embodiment, the present invention relates to these compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof mentioned in any other embodiment, wherein

R<3a>, R<3c>, R<3b>predstavljaju vodonik, halo, -NR<7a>R<7b>, ili -O-C1-4alkil; naročito, R<3a>, R<3c>, R<3b>predstavljaju halo, -NR<7a>R<7b>, ili -O-C1-4alkil; R<3a>, R<3c>, R<3b> represent hydrogen, halo, -NR<7a>R<7b>, or -O-C1-4alkyl; in particular, R<3a>, R<3c>, R<3b> represent halo, -NR<7a>R<7b>, or -O-C1-4alkyl;

R<4a>, R<4c>, R<4b>predstavljaju vodonik. R<4a>, R<4c>, R<4b>represent hydrogen.

[0144] U jednom otelotvorenju, predmetni pronalazak se odnosi na ova jedinjenja formule (I) i njihove farmaceutski prihvatljive adicione soli i solvate, ili bilo koju njihovu podgrupu pomenutu u bilo kom drugom otelotvorenju, pri čemu [0144] In one embodiment, the present invention relates to these compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof mentioned in any other embodiment, wherein

R<3a>, R<3c>, R<3b>, R<3d>i R<3e>predstavljaju vodonik, halo, -NR<7a>R<7b>, ili -O-C1-4alkil; naročito, R<3a>, R<3c>, R<3b>, R<3d>i R<3e>predstavljaju halo, -NR<7a>R<7b>, ili -O-C1-4alkil; R<3a>, R<3c>, R<3b>, R<3d> and R<3e> represent hydrogen, halo, -NR<7a>R<7b>, or -O-C1-4alkyl; in particular, R<3a>, R<3c>, R<3b>, R<3d> and R<3e> represent halo, -NR<7a>R<7b>, or -O-C1-4alkyl;

R<4a>, R<4c>, R<4b>, R<4d>, R<4e>, R<4f>i R<4g>predstavljaju vodonik. R<4a>, R<4c>, R<4b>, R<4d>, R<4e>, R<4f> and R<4g> represent hydrogen.

[0145] U jednom otelotvorenju, predmetni pronalazak se odnosi na ova jedinjenja formule (I) i njihove farmaceutski prihvatljive adicione soli i solvate, ili bilo koju njihovu podgrupu pomenutu u bilo kom drugom otelotvorenju, pri čemu [0145] In one embodiment, the present invention relates to these compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof mentioned in any other embodiment, wherein

R<3a>, R<3c>, R<3b>predstavljaju vodonik, kada su R<4a>, R<4c>, R<4b>različiti od vodonika. R<3a>, R<3c>, R<3b>represent hydrogen, when R<4a>, R<4c>, R<4b>are different from hydrogen.

[0146] U jednom otelotvorenju, predmetni pronalazak se odnosi na ova jedinjenja formule (I) i njihove farmaceutski prihvatljive adicione soli i solvate, ili bilo koju njihovu podgrupu pomenutu u bilo kom drugom otelotvorenju, pri čemu [0146] In one embodiment, the present invention relates to these compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof mentioned in any other embodiment, wherein

R<3a>R<3c>, R<3b>, R<3d>, R<3e>predstavljaju vodonik, kada su R<4a>, R<4c>, R<4b>, R<4d>, R<4e>, R<4f>, R<4g>različiti od vodonika. R<3a>R<3c>, R<3b>, R<3d>, R<3e>are hydrogen, when R<4a>, R<4c>, R<4b>, R<4d>, R<4e>, R<4f>, R<4g>are different from hydrogen.

[0147] U jednom otelotvorenju, predmetni pronalazak se odnosi na ova jedinjenja formule (I) i njihove farmaceutski prihvatljive adicione soli i solvate, ili bilo koju njihovu podgrupu pomenutu u bilo kom drugom otelotvorenju, pri čemu R<4a>, R<4c>, R<4b>predstavljaju vodonik, kada su R<3a>, R<3c>, R<3b>različiti od vodonika. [0147] In one embodiment, the present invention relates to these compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates, or any of their subgroups mentioned in any other embodiment, wherein R<4a>, R<4c>, R<4b> represent hydrogen, when R<3a>, R<3c>, R<3b> are different from hydrogen.

[0148] U jednom otelotvorenju, predmetni pronalazak se odnosi na ova jedinjenja formule (I) i njihove farmaceutski prihvatljive adicione soli i solvate, ili bilo koju njihovu podgrupu pomenutu u bilo kom drugom otelotvorenju, pri čemu R<4a>, R<4c>, R<4b>, R<4d>, R<4e>, R<4f>, R<4g>predstavljaju vodonik, kada su R<3a>, R<3c>, R<3b>, R<3d>, R<3e>različiti od vodonika. [0148] In one embodiment, the present invention relates to these compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof mentioned in any other embodiment, wherein R<4a>, R<4c>, R<4b>, R<4d>, R<4e>, R<4f>, R<4g> represent hydrogen, when R<3a>, R<3c>, R<3b>, R<3d>, R<3e> different from hydrogen.

[0149] U jednom otelotvorenju, predmetni pronalazak se odnosi na ova jedinjenja formule (I) i njihove farmaceutski prihvatljive adicione soli i solvate, ili bilo koju njihovu podgrupu pomenutu u bilo kom drugom otelotvorenju, pri čemu Ar predstavlja 10-člani biciklični aromatični sistem prstenova koji se sastoji od dva kondenzovana 6-člana prstena, [0149] In one embodiment, the present invention relates to these compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof mentioned in any other embodiment, wherein Ar represents a 10-membered bicyclic aromatic ring system consisting of two fused 6-membered rings,

pri čemu je najmanje 1 atom ugljenika prstena B zamenjen atomom azota; wherein at least 1 carbon atom of ring B is replaced by a nitrogen atom;

pri čemu je opciono 1 dodatni atom ugljenika prstena A ili prstena B zamenjen atomom azota, pod uslovom da, kada atom azota zamenjuje jedan od dva kondenzovana atoma ugljenika, karbonilna grupa je prisutna u navedenom bicikličnom aromatičnom sistemu prstenova; wherein optionally 1 additional carbon atom of ring A or ring B is replaced by a nitrogen atom, provided that, when the nitrogen atom replaces one of the two fused carbon atoms, a carbonyl group is present in said bicyclic aromatic ring system;

1 1

Ar je opciono supstituisan prema bilo kom drugom otelotvorenju. Ar is optionally substituted according to any other embodiment.

[0150] U jednom otelotvorenju, predmetni pronalazak se odnosi na ova jedinjenja formule (I) i njihove farmaceutski prihvatljive adicione soli i solvate, ili bilo koju njihovu podgrupu pomenutu u bilo kom drugom otelotvorenju, pri čemu Ar predstavlja 10-člani biciklični aromatični sistem prstenova koji se sastoji od dva kondenzovana 6-člana prstena, [0150] In one embodiment, the present invention relates to these compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof mentioned in any other embodiment, wherein Ar represents a 10-membered bicyclic aromatic ring system consisting of two fused 6-membered rings,

pri čemu je najmanje 1 atom ugljenika prstena B zamenjen atomom azota; wherein at least 1 carbon atom of ring B is replaced by a nitrogen atom;

pri čemu je opciono 1 dodatni atom ugljenika prstena A ili prstena B zamenjen atomom azota, pod uslovom da, kada atom azota zamenjuje jedan od dva kondenzovana atoma ugljenika, karbonilna grupa je prisutna u navedenom bicikličnom aromatičnom sistemu prstenova; Ar je opciono supstituisan sa jednim, dva, tri ili četiri supstituenta od kojih je svaki nezavisno izabran iz grupe koju čine halo, -OH, -NH2, -NH-C1-4alkil, -N(C1-wherein optionally 1 additional carbon atom of ring A or ring B is replaced by a nitrogen atom, provided that, when the nitrogen atom replaces one of the two fused carbon atoms, a carbonyl group is present in said bicyclic aromatic ring system; Ar is optionally substituted with one, two, three or four substituents each independently selected from the group consisting of halo, -OH, -NH2, -NH-C1-4alkyl, -N(C1-

4alkil)2, -NHR<10d>, -NR<10c>R<10d>, cijano, -CF3, -C(=O)-NH2, -C(=O)-NH-C1-4alkil, -C(=O)-C1-4alkil, C1-4alkiloksi, -C(=O)-O-C1-4alkil, C3-6cikloalkil, C2-6alkenil, C1-4alkil supstituisan jednim C1-4alkiloksi i C1-4alkil opciono supstituisan jednim -NR<10a>R<10b>; 4alkyl)2, -NHR<10d>, -NR<10c>R<10d>, cyano, -CF3, -C(=O)-NH2, -C(=O)-NH-C1-4alkyl, -C(=O)-C1-4alkyl, C1-4alkyloxy, -C(=O)-O-C1-4alkyl, C3-6cycloalkyl, C2-6alkenyl, C1-4alkyl. substituted with one C1-4alkyloxy and C1-4alkyl optionally substituted with one -NR<10a>R<10b>;

naročito, Ar je opciono supstituisan sa jednim, dva, tri ili četiri supstituenta od kojih je svaki nezavisno izabran iz grupe koju čine halo, -OH, -NH2, -NH-C1-4alkil, - N(C1-in particular, Ar is optionally substituted with one, two, three or four substituents each independently selected from the group consisting of halo, -OH, -NH2, -NH-C1-4alkyl, -N(C1-

4alkil)2, cijano, -CF3, -C(=O)-NH-C1-4alkil, -C(=O)-C1-4alkil, C1-4alkiloksi i C1-4alkil opciono supstituisan jednim -NR<10a>R<10b>; 4alkyl)2, cyano, -CF3, -C(=O)-NH-C1-4alkyl, -C(=O)-C1-4alkyl, C1-4alkyloxy and C1-4alkyl optionally substituted by one -NR<10a>R<10b>;

[0151] U jednom otelotvorenju, predmetni pronalazak se odnosi na ova jedinjenja formule (I) i njihove farmaceutski prihvatljive adicione soli i solvate, ili bilo koju njihovu podgrupu pomenutu u bilo kom drugom otelotvorenju, pri čemu [0151] In one embodiment, the present invention relates to these compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof mentioned in any other embodiment, wherein

1 1 1 1

Ar predstavlja 10-člani biciklični aromatični sistem prstenova koji se sastoji od dva kondenzovana 6-člana prstena sledeće strukture, Ar represents a 10-membered bicyclic aromatic ring system consisting of two fused 6-membered rings of the following structure,

pri čemu je opciono 1 dodatni atom ugljenika prstena A ili prstena B zamenjen atomom azota, pod uslovom da, kada atom azota zamenjuje jedan od dva kondenzovana atoma ugljenika, karbonilna grupa je prisutna u navedenom bicikličnom aromatičnom sistemu prstenova; wherein optionally 1 additional carbon atom of ring A or ring B is replaced by a nitrogen atom, provided that, when the nitrogen atom replaces one of the two fused carbon atoms, a carbonyl group is present in said bicyclic aromatic ring system;

Ar je opciono supstituisan prema bilo kom drugom otelotvorenju. Ar is optionally substituted according to any other embodiment.

Biće jasno da It will be clear that

obuhvata bilo koji od sledećih sistema prstenova: includes any of the following ring systems:

[0152] U jednom otelotvorenju, predmetni pronalazak se odnosi na ova jedinjenja formule (I) i njihove farmaceutski prihvatljive adicione soli i solvate, ili bilo koju njihovu podgrupu pomenutu u bilo kom drugom otelotvorenju, pri čemu je Ar izabran iz grupe koju čine: In one embodiment, the present invention relates to these compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof mentioned in any other embodiment, wherein Ar is selected from the group consisting of:

1 2 1 2

pri čemu je svaki Ar opciono supstituisan prema bilo kom drugom otelotvorenju. U jednom otelotvorenju, predmetni pronalazak se odnosi na ova jedinjenja formule (I) i njihove farmaceutski prihvatljive adicione soli i solvate, ili bilo koju njihovu podgrupu pomenutu u bilo kom drugom otelotvorenju, pri čemu je Ar izabran iz grupe koju čine: wherein each Ar is optionally substituted according to any other embodiment. In one embodiment, the present invention relates to these compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof mentioned in any other embodiment, wherein Ar is selected from the group consisting of:

pri čemu je svaki Ar opciono supstituisan prema bilo kom drugom otelotvorenju. wherein each Ar is optionally substituted according to any other embodiment.

[0153] U jednom otelotvorenju, predmetni pronalazak se odnosi na ova jedinjenja formule (I) i njihove farmaceutski prihvatljive adicione soli i solvate, ili bilo koju njihovu podgrupu pomenutu u bilo kom drugom otelotvorenju, pri čemu je Ar izabran iz grupe koju čine: In one embodiment, the present invention relates to these compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof mentioned in any other embodiment, wherein Ar is selected from the group consisting of:

1 1

pri čemu je svaki Ar opciono supstituisan prema bilo kom drugom otelotvorenju. wherein each Ar is optionally substituted according to any other embodiment.

[0154] U jednom otelotvorenju, predmetni pronalazak se odnosi na ova jedinjenja formule (I) i njihove farmaceutski prihvatljive adicione soli i solvate, ili bilo koju njihovu podgrupu pomenutu u bilo kom drugom otelotvorenju, pri čemu je Ar izabran iz grupe koju čine: [0154] In one embodiment, the present invention relates to these compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof mentioned in any other embodiment, wherein Ar is selected from the group consisting of:

pri čemu je svaki Ar opciono supstituisan prema bilo kom drugom otelotvorenju. wherein each Ar is optionally substituted according to any other embodiment.

[0155] U jednom otelotvorenju, predmetni pronalazak se odnosi na ova jedinjenja formule (I) i njihove farmaceutski prihvatljive adicione soli i solvate, ili bilo koju njihovu podgrupu pomenutu u bilo kom drugom otelotvorenju, pri čemu je Ar izabran iz grupe koju čine: [0155] In one embodiment, the present invention relates to these compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof mentioned in any other embodiment, wherein Ar is selected from the group consisting of:

1 4 1 4

pri čemu je svaki Ar opciono supstituisan prema bilo kom drugom otelotvorenju. wherein each Ar is optionally substituted according to any other embodiment.

[0156] U jednom otelotvorenju, predmetni pronalazak se odnosi na ova jedinjenja formule (I) i njihove farmaceutski prihvatljive adicione soli i solvate, ili bilo koju njihovu podgrupu pomenutu u bilo kom drugom otelotvorenju, pri čemu je Ar [0156] In one embodiment, the present invention relates to these compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof mentioned in any other embodiment, wherein Ar is

pri čemu je Ar opciono supstituisan prema bilo kom drugom otelotvorenju. wherein Ar is optionally substituted according to any other embodiment.

[0157] U jednom otelotvorenju, predmetni pronalazak se odnosi na ova jedinjenja formule (I) i njihove farmaceutski prihvatljive adicione soli i solvate, ili bilo koju njihovu podgrupu pomenutu u bilo kom drugom otelotvorenju, pri čemu Ar nije [0157] In one embodiment, the present invention relates to these compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof mentioned in any other embodiment, wherein Ar is not

pri čemu je Ar opciono supstituisan prema bilo kom drugom otelotvorenju. wherein Ar is optionally substituted according to any other embodiment.

[0158] U jednom otelotvorenju, predmetni pronalazak se odnosi na ova jedinjenja formule (I) i njihove farmaceutski prihvatljive adicione soli i solvate, ili bilo koju njihovu podgrupu pomenutu u bilo kom drugom otelotvorenju, pri čemu Ar predstavlja [0158] In one embodiment, the present invention relates to these compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof mentioned in any other embodiment, wherein Ar represents

1 1

pri čemu je Ar supstituisan sa jednim, dva, tri ili četiri supstituenta od kojih je svaki nezavisno izabran iz grupe koju čine halo, -NH2, -NH-C1-4alkil, -N(C1-4alkil)2, -NHR<10d>, -NR<10c>R<10d>. wherein Ar is substituted with one, two, three or four substituents each independently selected from the group consisting of halo, -NH2, -NH-C1-4alkyl, -N(C1-4alkyl)2, -NHR<10d>, -NR<10c>R<10d>.

[0159] U jednom otelotvorenju, predmetni pronalazak se odnosi na ova jedinjenja formule (I) i njihove farmaceutski prihvatljive adicione soli i solvate, ili bilo koju njihovu podgrupu pomenutu u bilo kom drugom otelotvorenju, pri čemu Ar predstavlja [0159] In one embodiment, the present invention relates to these compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof mentioned in any other embodiment, wherein Ar represents

pri čemu je Ar supstituisan jednim supstituentom izabranim iz grupe koju čine -NH2, -NH-C1- wherein Ar is substituted with one substituent selected from the group consisting of -NH2, -NH-C1-

4alkil, -N(C1-4alkil)2, -NHR<10d>, -NR<10c>R<10d>; i opciono je supstituisan halo supstituentom; 4alkyl, -N(C1-4alkyl)2, -NHR<10d>, -NR<10c>R<10d>; and is optionally substituted with a halo substituent;

R<10c>i R<10d>svaki nezavisno predstavlja C1-4alkil supstituisan sa jednim, dva ili tri halo supstituenta; ili C1-4alkil supstituisan jednim C3-6cikloalkil supstituentom. R<10c> and R<10d> each independently represents C1-4 alkyl substituted with one, two or three halo substituents; or C1-4alkyl substituted with one C3-6cycloalkyl substituent.

[0160] U jednom otelotvorenju, predmetni pronalazak se odnosi na ova jedinjenja formule (I) i njihove farmaceutski prihvatljive adicione soli i solvate, ili bilo koju njihovu podgrupu pomenutu u bilo kom drugom otelotvorenju, pri čemu Ar predstavlja [0160] In one embodiment, the present invention relates to these compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof mentioned in any other embodiment, wherein Ar represents

pri čemu je Ar supstituisan na poziciji označenoj sa α, supstituentom izabranim iz grupe koju čine -NH2, -NH-C1-4alkil, -N(C1-4alkil)2, -NHR<10d>, -NR<10c>R<10d>; i pri čemu je Ar opciono supstituisan na poziciji označenoj sa β, halo supstituentom. wherein Ar is substituted at the position indicated by α, with a substituent selected from the group consisting of -NH2, -NH-C1-4alkyl, -N(C1-4alkyl)2, -NHR<10d>, -NR<10c>R<10d>; and wherein Ar is optionally substituted at the position indicated by β, a halo substituent.

[0161] U jednom otelotvorenju, predmetni pronalazak se odnosi na ova jedinjenja formule (I) i njihove farmaceutski prihvatljive adicione soli i solvate, ili bilo koju njihovu podgrupu pomenutu u bilo kom drugom otelotvorenju, pri čemu Ar predstavlja [0161] In one embodiment, the present invention relates to these compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof mentioned in any other embodiment, wherein Ar represents

1 1

pri čemu je Ar supstituisan na poziciji označenoj sa α, supstituentom izabranim iz grupe koju čine -NH2, -NH-C1-4alkil, -N(C1-4alkil)2, -NHR<10d>, -NR<10c>R<10d>; i pri čemu je Ar opciono supstituisan na poziciji označenoj sa β, halo supstituentom; wherein Ar is substituted at the position indicated by α, with a substituent selected from the group consisting of -NH2, -NH-C1-4alkyl, -N(C1-4alkyl)2, -NHR<10d>, -NR<10c>R<10d>; and wherein Ar is optionally substituted at the position indicated by β, a halo substituent;

R<10c>i R<10d>svaki nezavisno predstavlja C1-4alkil supstituisan sa jednim, dva ili tri halo supstituenta; ili C1-4alkil supstituisan jednim C3-6cikloalkil supstituentom. R<10c> and R<10d> each independently represents C1-4 alkyl substituted with one, two or three halo substituents; or C1-4alkyl substituted with one C3-6cycloalkyl substituent.

[0162] U jednom otelotvorenju, predmetni pronalazak se odnosi na ova jedinjenja formule (I) i njihove farmaceutski prihvatljive adicione soli i solvate, ili bilo koju njihovu podgrupu pomenutu u bilo kom drugom otelotvorenju, pri čemu Ar predstavlja [0162] In one embodiment, the present invention relates to these compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof mentioned in any other embodiment, wherein Ar represents

pri čemu je Ar supstituisan na poziciji označenoj sa β, halo supstituentom; konkretno hlorom ili bromom; konkretnije bromom. wherein Ar is substituted at the position indicated by β, a halo substituent; specifically chlorine or bromine; more specifically bromine.

[0163] U jednom otelotvorenju, predmetni pronalazak se odnosi na ova jedinjenja formule (I) i njihove farmaceutski prihvatljive adicione soli i solvate, ili bilo koju njihovu podgrupu pomenutu u bilo kom drugom otelotvorenju, pri čemu Het predstavlja (a-1); Q<1>predstavlja CR<6a>; Q<2>predstavlja CR<6b>; i Ar predstavlja [0163] In one embodiment, the present invention relates to these compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof mentioned in any other embodiment, wherein Het represents (a-1); Q<1> represents CR<6a>; Q<2> represents CR<6b>; and Ar represents

pri čemu je Ar supstituisan na poziciji označenoj sa β, halo supstituentom; konkretno hlorom ili bromom; konkretnije bromom. wherein Ar is substituted at the position indicated by β, a halo substituent; specifically chlorine or bromine; more specifically bromine.

[0164] U jednom otelotvorenju, predmetni pronalazak se odnosi na ova jedinjenja formule (I) i njihove farmaceutski prihvatljive adicione soli i solvate, ili bilo koju njihovu podgrupu pomenutu u bilo kom drugom otelotvorenju, pri čemu je Ar supstituisan jednim supstituentom izabranim iz grupe koju čine -NH2, -NH-C1-4alkil, -N(C1-4alkil)2, -NHR<10d>, -NR<10c>R<10d>; i pri [0164] In one embodiment, the present invention relates to these compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof mentioned in any other embodiment, wherein Ar is substituted by one substituent selected from the group consisting of -NH2, -NH-C1-4alkyl, -N(C1-4alkyl)2, -NHR<10d>, -NR<10c>R<10d>; and at

1 1

čemu je Ar opciono supstituisan drugim supstituentom izabranim sa spiska supstituenata za Ar u bilo kom drugom otelotvorenju. wherein Ar is optionally substituted with another substituent selected from the list of substituents for Ar in any other embodiment.

[0165] U jednom otelotvorenju, predmetni pronalazak se odnosi na ova jedinjenja formule (I) i njihove farmaceutski prihvatljive adicione soli i solvate, ili bilo koju njihovu podgrupu pomenutu u bilo kom drugom otelotvorenju, pri čemu Ar predstavlja [0165] In one embodiment, the present invention relates to these compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof mentioned in any other embodiment, wherein Ar represents

opciono supstituisan prema bilo kom od drugih otelotvorenja. optionally substituted according to any of the other embodiments.

[0166] U jednom otelotvorenju, predmetni pronalazak se odnosi na ova jedinjenja formule (I) i njihove farmaceutski prihvatljive adicione soli i solvate, ili bilo koju njihovu podgrupu pomenutu u bilo kom drugom otelotvorenju, pri čemu Ar predstavlja [0166] In one embodiment, the present invention relates to these compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof mentioned in any other embodiment, wherein Ar represents

opciono supstituisan sa jednim, dva ili tri supstituenta od kojih je svaki nezavisno izabran iz grupe koju čine halo, -OH, -NH2, -NH-C1-4alkil, -N(C1-4alkil)2, cijano, - CF3, -C(=O)-NH-C1-4alkil, C1-4alkiloksi i C1-4alkil; optionally substituted with one, two or three substituents each independently selected from the group consisting of halo, -OH, -NH2, -NH-C1-4alkyl, -N(C1-4alkyl)2, cyano, -CF3, -C(=O)-NH-C1-4alkyl, C1-4alkyloxy and C1-4alkyl;

naročito opciono supstituisan sa jednim, dva ili tri supstituenta od kojih je svaki nezavisno izabran iz grupe koju čine halo, -NH2, -NH-C1-4alkil, cijano, -CF3, C1-especially optionally substituted with one, two or three substituents each independently selected from the group consisting of halo, -NH2, -NH-C1-4alkyl, cyano, -CF3, C1-

4alkiloksi i C1-4alkil; 4alkyloxy and C1-4alkyl;

konkretnije opciono supstituisan sa jednim, dva ili tri supstituenta od kojih je svaki nezavisno izabran iz grupe koju čine halo, ili -CF3; more specifically optionally substituted with one, two or three substituents each independently selected from the group consisting of halo, or -CF3;

konkretnije opciono supstituisan sa jednim ili dva halo supstituenta; more specifically optionally substituted with one or two halo substituents;

1 1

konkretnije supstituisan sa jednim ili dva halo supstituenta; more specifically substituted with one or two halo substituents;

još konkretnije supstituisan jednim halo supstituentom; more specifically substituted with one halo substituent;

najkonkretnije supstituisan jednim supstituentom hlorom. most specifically substituted with one chlorine substituent.

[0167] U jednom otelotvorenju, predmetni pronalazak se odnosi na ova jedinjenja formule (I) i njihove farmaceutski prihvatljive adicione soli i solvate, ili bilo koju njihovu podgrupu pomenutu u bilo kom drugom otelotvorenju, pri čemu Ar predstavlja [0167] In one embodiment, the present invention relates to these compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof mentioned in any other embodiment, wherein Ar represents

opciono supstituisan prema bilo kom od drugih otelotvorenja. optionally substituted according to any of the other embodiments.

[0168] U jednom otelotvorenju, predmetni pronalazak se odnosi na ova jedinjenja formule (I) i njihove farmaceutski prihvatljive adicione soli i solvate, ili bilo koju njihovu podgrupu pomenutu u bilo kom drugom otelotvorenju, pri čemu Ar predstavlja [0168] In one embodiment, the present invention relates to these compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof mentioned in any other embodiment, wherein Ar represents

opciono supstituisan sa jednim, dva ili tri supstituenta od kojih je svaki nezavisno izabran iz grupe koju čine halo, -OH, -NH2, -NH-C1-4alkil, -N(C1-4alkil)2, cijano, -CF3, -C(=O)-NH-C1-4alkil, C1-4alkiloksi i C1-4alkil; optionally substituted with one, two or three substituents each independently selected from the group consisting of halo, -OH, -NH2, -NH-C1-4alkyl, -N(C1-4alkyl)2, cyano, -CF3, -C(=O)-NH-C1-4alkyl, C1-4alkyloxy and C1-4alkyl;

naročito opciono supstituisan sa jednim, dva ili tri supstituenta od kojih je svaki nezavisno izabran iz grupe koju čine halo, -NH2, -NH-C1-4alkil, cijano, -CF3, C1-especially optionally substituted with one, two or three substituents each independently selected from the group consisting of halo, -NH2, -NH-C1-4alkyl, cyano, -CF3, C1-

4alkiloksi i C1-4alkil; 4alkyloxy and C1-4alkyl;

konkretnije opciono supstituisan sa jednim, dva ili tri supstituenta od kojih je svaki nezavisno izabran iz grupe koju čine halo, ili -CF3; more specifically optionally substituted with one, two or three substituents each independently selected from the group consisting of halo, or -CF3;

1 1

konkretnije opciono supstituisan sa jednim ili dva halo supstituenta; more specifically optionally substituted with one or two halo substituents;

konkretnije supstituisan sa jednim ili dva halo supstituenta; more specifically substituted with one or two halo substituents;

još konkretnije supstituisan jednim halo supstituentom; more specifically substituted with one halo substituent;

najkonkretnije supstituisan jednim supstituentom hlorom. most specifically substituted with one chlorine substituent.

[0169] U jednom otelotvorenju, predmetni pronalazak se odnosi na ova jedinjenja formule (I) i njihove farmaceutski prihvatljive adicione soli i solvate, ili bilo koju njihovu podgrupu pomenutu u bilo kom drugom otelotvorenju, pri čemu Het predstavlja (a-1); i [0169] In one embodiment, the present invention relates to these compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof mentioned in any other embodiment, wherein Het represents (a-1); and

Ar predstavlja Ar represents

opciono supstituisan sa jednim, dva ili tri supstituenta od kojih je svaki nezavisno izabran iz grupe koju čine halo, -OH, -NH2, -NH-C1-4alkil, -N(C1-4alkil)2, cijano, -CF3, -C(=O)-NH-C1-4alkil, C1-4alkiloksi i C1-4alkil; optionally substituted with one, two or three substituents each independently selected from the group consisting of halo, -OH, -NH2, -NH-C1-4alkyl, -N(C1-4alkyl)2, cyano, -CF3, -C(=O)-NH-C1-4alkyl, C1-4alkyloxy and C1-4alkyl;

naročito opciono supstituisan sa jednim, dva ili tri supstituenta od kojih je svaki nezavisno izabran iz grupe koju čine halo, -NH2, -NH-C1-4alkil, cijano, -CF3, C1-especially optionally substituted with one, two or three substituents each independently selected from the group consisting of halo, -NH2, -NH-C1-4alkyl, cyano, -CF3, C1-

4alkiloksi i C1-4alkil; 4alkyloxy and C1-4alkyl;

konkretnije opciono supstituisan sa jednim, dva ili tri supstituenta od kojih je svaki nezavisno izabran iz grupe koju čine halo, ili -CF3; more specifically optionally substituted with one, two or three substituents each independently selected from the group consisting of halo, or -CF3;

konkretnije opciono supstituisan sa jednim ili dva halo supstituenta; more specifically optionally substituted with one or two halo substituents;

konkretnije supstituisan sa jednim ili dva halo supstituenta; more specifically substituted with one or two halo substituents;

još konkretnije supstituisan jednim halo supstituentom; more specifically substituted with one halo substituent;

11 11

najkonkretnije supstituisan jednim supstituentom hlorom. most specifically substituted with one chlorine substituent.

[0170] U jednom otelotvorenju, predmetni pronalazak se odnosi na ova jedinjenja formule (I) i njihove farmaceutski prihvatljive adicione soli i solvate, ili bilo koju njihovu podgrupu pomenutu u bilo kom drugom otelotvorenju, pri čemu [0170] In one embodiment, the present invention relates to these compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof mentioned in any other embodiment, wherein

Het predstavlja (a-1); i Het represents (a-1); and

Ar predstavlja Ar represents

konkretnije, Ar predstavlja more specifically, Ar represents

[0171] U jednom otelotvorenju, predmetni pronalazak se odnosi na ova jedinjenja formule (I) i njihove farmaceutski prihvatljive adicione soli i solvate, ili bilo koju njihovu podgrupu pomenutu u bilo kom drugom otelotvorenju, pri čemu Ar predstavlja [0171] In one embodiment, the present invention relates to these compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof mentioned in any other embodiment, wherein Ar represents

naročito, Ar predstavlja in particular, Ar represents

konkretnije, Ar predstavlja more specifically, Ar represents

[0172] U jednom otelotvorenju, predmetni pronalazak se odnosi na ova jedinjenja formule (I) i njihove farmaceutski prihvatljive adicione soli i solvate, ili bilo koju njihovu podgrupu pomenutu u bilo kom drugom otelotvorenju, pri čemu R<5b>, R<5g>i R<5h>predstavljaju vodonik. [0172] In one embodiment, the present invention relates to these compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof mentioned in any other embodiment, wherein R<5b>, R<5g> and R<5h> represent hydrogen.

[0173] U jednom otelotvorenju, predmetni pronalazak se odnosi na ova jedinjenja formule (I) i njihove farmaceutski prihvatljive adicione soli i solvate, ili bilo koju njihovu podgrupu pomenutu u bilo kom drugom otelotvorenju, pri čemu Q<1>predstavlja CR<6a>; i Q<2>predstavlja CR<6b>. [0173] In one embodiment, the present invention relates to these compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof mentioned in any other embodiment, wherein Q<1>represents CR<6a>; and Q<2>represents CR<6b>.

[0174] U jednom otelotvorenju, predmetni pronalazak se odnosi na ova jedinjenja formule (I) i njihove farmaceutski prihvatljive adicione soli i solvate, ili bilo koju njihovu podgrupu pomenutu u bilo kom drugom otelotvorenju, pri čemu X predstavlja -O-; Q<1>predstavlja CR<6a>; i Q<2>predstavlja CR<6b>. [0174] In one embodiment, the present invention relates to these compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof mentioned in any other embodiment, wherein X represents -O-; Q<1> represents CR<6a>; and Q<2>represents CR<6b>.

[0175] U jednom otelotvorenju, predmetni pronalazak se odnosi na ova jedinjenja formule (I) i njihove farmaceutski prihvatljive adicione soli i solvate, ili bilo koju njihovu podgrupu pomenutu u bilo kom drugom otelotvorenju, pri čemu X predstavlja -O-; Q<1>predstavlja CH; i Q<2>predstavlja CR<H>. [0175] In one embodiment, the present invention relates to these compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof mentioned in any other embodiment, wherein X represents -O-; Q<1>represents CH; and Q<2>represents CR<H>.

[0176] U jednom otelotvorenju, predmetni pronalazak se odnosi na ova jedinjenja formule (I) i njihove farmaceutski prihvatljive adicione soli i solvate, ili bilo koju njihovu podgrupu pomenutu u bilo kom drugom otelotvorenju, pri čemu [0176] In one embodiment, the present invention relates to these compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof mentioned in any other embodiment, wherein

R<5b>, R<5g>i R<5h>predstavljaju vodonik; R<5b>, R<5g> and R<5h> represent hydrogen;

Y predstavlja -CH2- ili -CF2-; naročito, Y predstavlja -CH2-; i Het predstavlja (a-1); Y represents -CH2- or -CF2-; in particular, Y represents -CH2-; and Het represents (a-1);

Q<1>predstavlja CR<6a>; i Q<2>predstavlja CR<6b>; naročito pri čemu Q<1>predstavlja CH; i Q<2>predstavlja CH. Q<1> represents CR<6a>; and Q<2>represents CR<6b>; especially where Q<1> represents CH; and Q<2>represents CH.

[0177] U jednom otelotvorenju, predmetni pronalazak se odnosi na ova jedinjenja formule (I) i njihove farmaceutski prihvatljive adicione soli i solvate, ili bilo koju njihovu podgrupu pomenutu u bilo kom drugom otelotvorenju, pri čemu [0177] In one embodiment, the present invention relates to these compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof mentioned in any other embodiment, wherein

R<5b>, R<5g>i R<5h>predstavljaju vodonik; Y predstavlja -O-; i R<5b>, R<5g> and R<5h> represent hydrogen; Y represents -O-; and

Het predstavlja (a-1); Het represents (a-1);

Q<1>predstavlja CR<6a>; i Q<2>predstavlja CR<6b>; naročito pri čemu Q<1>predstavlja CH; i Q<2>predstavlja CH. Q<1> represents CR<6a>; and Q<2>represents CR<6b>; especially where Q<1> represents CH; and Q<2>represents CH.

[0178] U jednom otelotvorenju, predmetni pronalazak se odnosi na ova jedinjenja formule (I) i njihove farmaceutski prihvatljive adicione soli i solvate, ili bilo koju njihovu podgrupu pomenutu u bilo kom drugom otelotvorenju, pri čemu Q<2>predstavlja CR<6b>. [0178] In one embodiment, the present invention relates to these compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof mentioned in any other embodiment, wherein Q<2>represents CR<6b>.

[0179] U jednom otelotvorenju, predmetni pronalazak se odnosi na ova jedinjenja formule (I) i njihove farmaceutski prihvatljive adicione soli i solvate, ili bilo koju njihovu podgrupu pomenutu u bilo kom drugom otelotvorenju, pri čemu Z predstavlja -X-CR<5a>R<5b>-. [0179] In one embodiment, the present invention relates to these compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof mentioned in any other embodiment, wherein Z represents -X-CR<5a>R<5b>-.

[0180] U jednom otelotvorenju, predmetni pronalazak se odnosi na ova jedinjenja formule (I) i njihove farmaceutski prihvatljive adicione soli i solvate, ili bilo koju njihovu podgrupu pomenutu u bilo kom drugom otelotvorenju, pri čemu Z predstavlja -O-CH2-. [0180] In one embodiment, the present invention relates to these compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof mentioned in any other embodiment, wherein Z represents -O-CH2-.

11 11

[0181] U jednom otelotvorenju, predmetni pronalazak se odnosi na ova jedinjenja formule (I) i njihove farmaceutski prihvatljive adicione soli i solvate, ili bilo koju njihovu podgrupu pomenutu u bilo kom drugom otelotvorenju, pri čemu Z predstavlja -X-CR<5a>R<5b>-; X predstavlja -O-; i R<5a>i R<5b>predstavljaju vodonik. [0181] In one embodiment, the present invention relates to these compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof mentioned in any other embodiment, wherein Z represents -X-CR<5a>R<5b>-; X represents -O-; and R<5a> and R<5b>represent hydrogen.

[0182] U jednom otelotvorenju, predmetni pronalazak se odnosi na ova jedinjenja formule (I) i njihove farmaceutski prihvatljive adicione soli i solvate, ili bilo koju njihovu podgrupu pomenutu u bilo kom drugom otelotvorenju, pri čemu X predstavlja -O- ili -NR<11>-; naročito, X predstavlja -O-. [0182] In one embodiment, the present invention relates to these compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof mentioned in any other embodiment, wherein X represents -O- or -NR<11>-; in particular, X represents -O-.

[0183] U jednom otelotvorenju, predmetni pronalazak se odnosi na ova jedinjenja formule (I) i njihove farmaceutski prihvatljive adicione soli i solvate, ili bilo koju njihovu podgrupu pomenutu u bilo kom drugom otelotvorenju, pri čemu R<7a>i R<7b>predstavljaju vodonik. [0183] In one embodiment, the present invention relates to these compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof mentioned in any other embodiment, wherein R<7a> and R<7b> represent hydrogen.

[0184] U jednom otelotvorenju, predmetni pronalazak se odnosi na ova jedinjenja formule (I) i njihove farmaceutski prihvatljive adicione soli i solvate, ili bilo koju njihovu podgrupu pomenutu u bilo kom drugom otelotvorenju, pri čemu Het predstavlja (a-1); R<3a>predstavlja -NR<7a>R<7b>; i R<7a>i R<7b>predstavljaju vodonik. [0184] In one embodiment, the present invention relates to these compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof mentioned in any other embodiment, wherein Het represents (a-1); R<3a>represents -NR<7a>R<7b>; and R<7a> and R<7b>represent hydrogen.

[0185] U jednom otelotvorenju, predmetni pronalazak se odnosi na ova jedinjenja formule (I) i njihove farmaceutski prihvatljive adicione soli i solvate, ili bilo koju njihovu podgrupu pomenutu u bilo kom drugom otelotvorenju, pri čemu Ar predstavlja 10-člani biciklični aromatični sistem prstenova koji se sastoji od dva kondenzovana 6-člana prstena, [0185] In one embodiment, the present invention relates to these compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof mentioned in any other embodiment, wherein Ar represents a 10-membered bicyclic aromatic ring system consisting of two fused 6-membered rings,

pri čemu je najmanje 1 atom ugljenika prstena B zamenjen atomom azota; pri čemu je opciono 1 dodatni atom ugljenika prstena A ili prstena B zamenjen atomom azota, pod uslovom da, kada atom azota zamenjuje jedan od dva kondenzovana atoma ugljenika, karbonil grupa je prisutna u navedenom bicikličnom aromatičnom sistemu prstenova; wherein at least 1 carbon atom of ring B is replaced by a nitrogen atom; wherein optionally 1 additional carbon atom of ring A or ring B is replaced by a nitrogen atom, provided that, when the nitrogen atom replaces one of the two fused carbon atoms, a carbonyl group is present in said bicyclic aromatic ring system;

Ar je opciono supstituisan jednim supstituentom izabranim iz grupe koju čine halo, -OH, -NH2, -NH-C1-4alkil, -N(C1-4alkil)2, cijano, -CF3, -C(=O)-NH-C1-4alkil, - C(=O)-C1-4alkil, C1-4alkiloksi i C1-4alkil opciono supstituisan jednim - NR<10a>R<10b>; Ar is optionally substituted with one substituent selected from the group consisting of halo, -OH, -NH2, -NH-C1-4alkyl, -N(C1-4alkyl)2, cyano, -CF3, -C(=O)-NH-C1-4alkyl, - C(=O)-C1-4alkyl, C1-4alkyloxy and C1-4alkyl optionally substituted with one - NR<10a>R<10b>;

R<3a>, R<3b>i R<3c>predstavljaju -NR<7a>R<7b>; i R<7a>i R<7b>predstavljaju vodonik. R<3a>, R<3b> and R<3c> represent -NR<7a>R<7b>; and R<7a> and R<7b>represent hydrogen.

[0186] U jednom otelotvorenju, predmetni pronalazak se odnosi na ova jedinjenja formule (I) i njihove farmaceutski prihvatljive adicione soli i solvate, ili bilo koju njihovu podgrupu pomenutu u bilo kom drugom otelotvorenju, pri čemu Ar predstavlja 10-člani biciklični aromatični sistem prstenova koji se sastoji od dva kondenzovana 6-člana prstena, [0186] In one embodiment, the present invention relates to these compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof mentioned in any other embodiment, wherein Ar represents a 10-membered bicyclic aromatic ring system consisting of two fused 6-membered rings,

pri čemu je najmanje 1 atom ugljenika prstena B zamenjen atomom azota; wherein at least 1 carbon atom of ring B is replaced by a nitrogen atom;

pri čemu je opciono 1 dodatni atom ugljenika prstena A ili prstena B zamenjen atomom azota, pod uslovom da, kada atom azota zamenjuje jedan od dva kondenzovana atoma ugljenika, karbonilna grupa je prisutna u navedenom bicikličnom aromatičnom sistemu prstenova; wherein optionally 1 additional carbon atom of ring A or ring B is replaced by a nitrogen atom, provided that, when the nitrogen atom replaces one of the two fused carbon atoms, a carbonyl group is present in said bicyclic aromatic ring system;

Ar je opciono supstituisan jednim supstituentom izabranim iz grupe koju čine halo, -OH, -NH2, -NH-C1-4alkil, -N(C1-4alkil)2, cijano, -CF3, -C(=O)-NH-C1-4alkil, - C(=O)-C1-4alkil, C1-4alkiloksi i C1-4alkil opciono supstituisan jednim - NR<10a>R<10b>; Ar is optionally substituted with one substituent selected from the group consisting of halo, -OH, -NH2, -NH-C1-4alkyl, -N(C1-4alkyl)2, cyano, -CF3, -C(=O)-NH-C1-4alkyl, - C(=O)-C1-4alkyl, C1-4alkyloxy and C1-4alkyl optionally substituted with one - NR<10a>R<10b>;

R<3a>, R<3c>, R<3b>, R<3d>i R<3e>predstavljaju -NR<7a>R<7a>; i R<7a>i R<7b>predstavljaju vodonik. R<3a>, R<3c>, R<3b>, R<3d>and R<3e> represent -NR<7a>R<7a>; and R<7a> and R<7b>represent hydrogen.

[0187] U jednom otelotvorenju, predmetni pronalazak se odnosi na ova jedinjenja formule (I) i njihove farmaceutski prihvatljive adicione soli i solvate, ili bilo koju njihovu podgrupu pomenutu u bilo kom drugom otelotvorenju, pri čemu R<3a>, R<3b>i R<3c>ne predstavljaju halo. [0187] In one embodiment, the present invention relates to these compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof mentioned in any other embodiment, wherein R<3a>, R<3b> and R<3c> do not represent halo.

11 11

[0188] U jednom otelotvorenju, predmetni pronalazak se odnosi na ova jedinjenja formule (I) i njihove farmaceutski prihvatljive adicione soli i solvate, ili bilo koju njihovu podgrupu pomenutu u bilo kom drugom otelotvorenju, pri čemu R<3a>, R<3c>, R<3b>, R<3d>i R<3e>ne predstavljaju halo. [0188] In one embodiment, the present invention relates to these compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof mentioned in any other embodiment, wherein R<3a>, R<3c>, R<3b>, R<3d> and R<3e> do not represent halo.

[0189] U jednom otelotvorenju, predmetni pronalazak se odnosi na ova jedinjenja formule (I) i njihove farmaceutski prihvatljive adicione soli i solvate, ili bilo koju njihovu podgrupu pomenutu u bilo kom drugom otelotvorenju, pri čemu [0189] In one embodiment, the present invention relates to these compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof mentioned in any other embodiment, wherein

R<3a>, R<3b>i R<3c>predstavljaju -NR<7a>R<7b>; R<3a>, R<3b> and R<3c> represent -NR<7a>R<7b>;

R<7a>predstavlja vodonik; R<7a> represents hydrogen;

R<7b>predstavlja vodonik. R<7b>represents hydrogen.

[0190] U jednom otelotvorenju, predmetni pronalazak se odnosi na ova jedinjenja formule (I) i njihove farmaceutski prihvatljive adicione soli i solvate, ili bilo koju njihovu podgrupu pomenutu u bilo kom drugom otelotvorenju, pri čemu R<3a>, R<3b>i R<3c>predstavljaju -NH2. [0190] In one embodiment, the present invention relates to these compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof mentioned in any other embodiment, wherein R<3a>, R<3b> and R<3c> represent -NH2.

[0191] U jednom otelotvorenju, predmetni pronalazak se odnosi na ova jedinjenja formule (I) i njihove farmaceutski prihvatljive adicione soli i solvate, ili bilo koju njihovu podgrupu pomenutu u bilo kom drugom otelotvorenju, pri čemu Ar predstavlja 10-člani biciklični aromatični sistem prstenova koji se sastoji od dva kondenzovana 6-člana prstena, [0191] In one embodiment, the present invention relates to these compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof mentioned in any other embodiment, wherein Ar represents a 10-membered bicyclic aromatic ring system consisting of two fused 6-membered rings,

pri čemu je najmanje 1 atom ugljenika prstena B zamenjen atomom azota; wherein at least 1 carbon atom of ring B is replaced by a nitrogen atom;

pri čemu je opciono 1 dodatni atom ugljenika prstena A ili prstena B zamenjen atomom azota, pod uslovom da, kada atom azota zamenjuje jedan od dva kondenzovana atoma wherein optionally 1 additional ring A or ring B carbon atom is replaced by a nitrogen atom, provided that, when the nitrogen atom replaces one of the two condensed atoms

11 11

ugljenika, karbonilna grupa je prisutna u navedenom bicikličnom aromatičnom sistemu prstenova; Ar je carbon, the carbonyl group is present in said bicyclic aromatic ring system; Ar is

opciono supstituisan jednim supstituentom izabranim iz grupe koju čine halo, - OH, -NH2, -NH-C1-4alkil, -N(C1-4alkil)2, cijano, -CF3, -C(=O)-NH-C1-4alkil, -C(=O)-C1-4alkil, C1-4alkiloksi i C1-4alkil opciono supstituisan jednim -NR<10a>R<10b>; optionally substituted with one substituent selected from the group consisting of halo, -OH, -NH2, -NH-C1-4alkyl, -N(C1-4alkyl)2, cyano, -CF3, -C(=O)-NH-C1-4alkyl, -C(=O)-C1-4alkyl, C1-4alkyloxy and C1-4alkyl optionally substituted with one -NR<10a>R<10b>;

Het predstavlja (a-1); R<3a>predstavlja -NR<7a>R<7b>; i R<7a>i R<7b>predstavljaju vodonik. Het represents (a-1); R<3a>represents -NR<7a>R<7b>; and R<7a> and R<7b>represent hydrogen.

[0192] U jednom otelotvorenju, predmetni pronalazak se odnosi na ova jedinjenja formule (I) i njihove farmaceutski prihvatljive adicione soli i solvate, ili bilo koju njihovu podgrupu pomenutu u bilo kom drugom otelotvorenju, pri čemu Ar predstavlja 10-člani biciklični aromatični sistem prstenova koji se sastoji od dva kondenzovana 6-člana prstena, [0192] In one embodiment, the present invention relates to these compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof mentioned in any other embodiment, wherein Ar represents a 10-membered bicyclic aromatic ring system consisting of two fused 6-membered rings,

pri čemu je najmanje 1 atom ugljenika prstena B zamenjen atomom azota; pri čemu je opciono 1 dodatni atom ugljenika prstena A ili prstena B zamenjen atomom azota, pod uslovom da, kada atom azota zamenjuje jedan od dva kondenzovana atoma ugljenika, karbonil grupa je prisutna u navedenom bicikličnom aromatičnom sistemu prstenova; Ar je supstituisan jednim supstituentom izabranim iz grupe koju čine halo, -OH, -NH2, -NH-C1-4alkil, -N(C1-4alkil)2, cijano, -CF3, -C(=O)-NH-C1-4alkil, -C(=O)-C1-4alkil, C1-4alkiloksi i C1-4alkil opciono supstituisan jednim -NR<10a>R<10b>; Het predstavlja (a-1); R<3a>predstavlja -NR<7a>R<7b>; i R<7a>i R<7b>predstavljaju vodonik. wherein at least 1 carbon atom of ring B is replaced by a nitrogen atom; wherein optionally 1 additional carbon atom of ring A or ring B is replaced by a nitrogen atom, provided that, when the nitrogen atom replaces one of the two fused carbon atoms, a carbonyl group is present in said bicyclic aromatic ring system; Ar is substituted with one substituent selected from the group consisting of halo, -OH, -NH2, -NH-C1-4alkyl, -N(C1-4alkyl)2, cyano, -CF3, -C(=O)-NH-C1-4alkyl, -C(=O)-C1-4alkyl, C1-4alkyloxy and C1-4alkyl optionally substituted with one -NR<10a>R<10b>; Het represents (a-1); R<3a>represents -NR<7a>R<7b>; and R<7a> and R<7b>represent hydrogen.

[0193] U jednom otelotvorenju, predmetni pronalazak se odnosi na ova jedinjenja formule (I) i njihove farmaceutski prihvatljive adicione soli i solvate, ili bilo koju njihovu podgrupu pomenutu u bilo kom drugom otelotvorenju, pri čemu Ar predstavlja [0193] In one embodiment, the present invention relates to these compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof mentioned in any other embodiment, wherein Ar represents

11 11

opciono supstituisan jednim supstituentom izabranim iz grupe koju čine halo, - OH, -NH2, -NH-C1-4alkil, -N(C1-4alkil)2, cijano, -CF3, -C(=O)-NH-C1-4alkil, C1-4alkiloksi i C1-4alkil; optionally substituted with one substituent selected from the group consisting of halo, -OH, -NH2, -NH-C1-4alkyl, -N(C1-4alkyl)2, cyano, -CF3, -C(=O)-NH-C1-4alkyl, C1-4alkyloxy and C1-4alkyl;

naročito opciono supstituisan jednim supstituentom izabranim iz grupe koju čine halo, -NH2, -NH-C1-4alkil, cijano, -CF3, C1-4alkiloksi i C1-4alkil; konkretnije opciono supstituisan jednim supstituentom izabranim iz grupe koju čine halo i -CF3; especially optionally substituted with one substituent selected from the group consisting of halo, -NH2, -NH-C1-4alkyl, cyano, -CF3, C1-4alkyloxy and C1-4alkyl; more specifically optionally substituted with one substituent selected from the group consisting of halo and -CF3;

konkretnije opciono supstituisan jednim halo supstituentom; more specifically optionally substituted with one halo substituent;

konkretnije supstituisan jednim halo supstituentom; more specifically substituted with one halo substituent;

još konkretnije supstituisan jednim supstituentom hlorom. more specifically substituted with one chlorine substituent.

[0194] U jednom otelotvorenju, predmetni pronalazak se odnosi na ova jedinjenja formule (I) i njihove farmaceutski prihvatljive adicione soli i solvate, ili bilo koju njihovu podgrupu pomenutu u bilo kom drugom otelotvorenju, pri čemu je Ar izabran iz grupe koju čine: [0194] In one embodiment, the present invention relates to these compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof mentioned in any other embodiment, wherein Ar is selected from the group consisting of:

pri čemu je svaki Ar opciono supstituisan prema bilo kom drugom otelotvorenju; naročito pri čemu je Ar opciono supstituisan jednim supstituentom kako je definisano u bilo kom drugom otelotvorenju. wherein each Ar is optionally substituted according to any other embodiment; particularly wherein Ar is optionally substituted with one substituent as defined in any other embodiment.

[0195] U jednom otelotvorenju, predmetni pronalazak se odnosi na ova jedinjenja formule (I) i njihove farmaceutski prihvatljive adicione soli i solvate, ili bilo koju njihovu podgrupu pomenutu u bilo kom drugom otelotvorenju, pri čemu je Ar izabran iz grupe koju čine: [0195] In one embodiment, the present invention relates to these compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof mentioned in any other embodiment, wherein Ar is selected from the group consisting of:

11 11

pri čemu je svaki Ar opciono supstituisan prema bilo kom drugom otelotvorenju; naročito pri čemu je Ar opciono supstituisan jednim supstituentom kako je definisano u bilo kom drugom otelotvorenju. wherein each Ar is optionally substituted according to any other embodiment; particularly wherein Ar is optionally substituted with one substituent as defined in any other embodiment.

[0196] U jednom otelotvorenju, predmetni pronalazak se odnosi na ova jedinjenja formule (I) i njihove farmaceutski prihvatljive adicione soli i solvate, ili bilo koju njihovu podgrupu pomenutu u bilo kom drugom otelotvorenju, pri čemu je Ar izabran iz grupe koju čine: [0196] In one embodiment, the present invention relates to these compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof mentioned in any other embodiment, wherein Ar is selected from the group consisting of:

pri čemu je svaki Ar opciono supstituisan prema bilo kom drugom otelotvorenju; naročito pri čemu je Ar opciono supstituisan jednim supstituentom kako je definisano u bilo kom drugom otelotvorenju. wherein each Ar is optionally substituted according to any other embodiment; particularly wherein Ar is optionally substituted with one substituent as defined in any other embodiment.

[0197] U jednom otelotvorenju, predmetni pronalazak se odnosi na ova jedinjenja formule (I) i njihove farmaceutski prihvatljive adicione soli i solvate, ili bilo koju njihovu podgrupu pomenutu u bilo kom drugom otelotvorenju, pri čemu je Ar izabran iz grupe koju čine: [0197] In one embodiment, the present invention relates to these compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof mentioned in any other embodiment, wherein Ar is selected from the group consisting of:

pri čemu je svaki Ar opciono supstituisan na poziciji α, supstituentom izabranim iz grupe koju čine -NH2, -NH-C1-4alkil, -N(C1-4alkil)2, -NHR<10d>i -NR<10c>R<10d>; R<10c>i R<10d>svaki nezavisno predstavlja C3-6cikloalkil; C3-6cikloalkil supstituisan sa jednim, dva ili tri supstituenta od kojih je svaki nezavisno izabran iz grupe koju čine halo, -OH i -O- wherein each Ar is optionally substituted in position α, with a substituent selected from the group consisting of -NH2, -NH-C1-4alkyl, -N(C1-4alkyl)2, -NHR<10d> and -NR<10c>R<10d>; R<10c> and R<10d> each independently represents C3-6cycloalkyl; C3-6cycloalkyl substituted with one, two or three substituents each independently selected from the group consisting of halo, -OH and -O-

11 11

C1-4alkil; C1-4alkil supstituisan sa jednim, dva ili tri supstituenta od kojih je svaki nezavisno izabran iz grupe koju čine halo, -OH i - O-C1-4alkil; ili C1-4alkil supstituisan jednim supstituentom izabranim iz grupe koju čine C3-6cikloalkil, R<13>i R<14>; C1-4alkyl; C1-4alkyl substituted with one, two or three substituents each independently selected from the group consisting of halo, -OH and -O-C1-4alkyl; or C1-4alkyl substituted with one substituent selected from the group consisting of C3-6cycloalkyl, R<13> and R<14>;

R<13>predstavlja 4- do 7-člani monociklični aromatični prsten koji sadrži jedan, dva ili tri heteroatoma, svaki nezavisno izabran od O, S, S(=O)pi N; ili 6- do 11-člani biciklični kondenzovani aromatični prsten koji sadrži jedan, dva ili tri heteroatoma, svaki nezavisno izabran od O, S, S(=O)pi N; R<13>represents a 4- to 7-membered monocyclic aromatic ring containing one, two or three heteroatoms, each independently selected from O, S, S(=O) and N; or a 6- to 11-membered bicyclic fused aromatic ring containing one, two or three heteroatoms, each independently selected from O, S, S(=O) and N;

navedeni 4- do 7-člani monociklični aromatični prsten ili 6- do 11-člani biciklični kondenzovani aromatični prsten je opciono supstituisan sa jednim ili dva supstituenta izabrana iz grupe koju čini C1-4alkil; said 4- to 7-membered monocyclic aromatic ring or 6- to 11-membered bicyclic fused aromatic ring is optionally substituted with one or two substituents selected from the group consisting of C1-4alkyl;

p predstavlja 1 ili 2; p represents 1 or 2;

R<14>predstavlja fenil opciono supstituisan sa jednim, dva ili tri supstituenta od kojih je svaki nezavisno izabran iz grupe koju čini halo. R<14> is phenyl optionally substituted with one, two or three substituents each independently selected from the group consisting of halo.

[0198] U jednom otelotvorenju, predmetni pronalazak se odnosi na ova jedinjenja formule (I) i njihove farmaceutski prihvatljive adicione soli i solvate, ili bilo koju njihovu podgrupu pomenutu u bilo kom drugom otelotvorenju, pri čemu je Ar izabran iz grupe koju čine: [0198] In one embodiment, the present invention relates to these compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof mentioned in any other embodiment, wherein Ar is selected from the group consisting of:

pri čemu je svaki Ar opciono supstituisan na poziciji α, supstituentom izabranim iz grupe koju čine -NH2, -NH-C1-4alkil, -N(C1-4alkil)2, -NHR<10d>i -NR<10c>R<10d>; i pri čemu je Ar opciono supstituisan na drugoj poziciji halo supstituentom. wherein each Ar is optionally substituted in position α, with a substituent selected from the group consisting of -NH2, -NH-C1-4alkyl, -N(C1-4alkyl)2, -NHR<10d> and -NR<10c>R<10d>; and wherein Ar is optionally substituted at the second position with a halo substituent.

[0199] U jednom otelotvorenju, predmetni pronalazak se odnosi na ova jedinjenja formule (I) i njihove farmaceutski prihvatljive adicione soli i solvate, ili bilo koju njihovu podgrupu pomenutu u bilo kom drugom otelotvorenju, pri čemu je Ar izabran iz grupe koju čine: [0199] In one embodiment, the present invention relates to these compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof mentioned in any other embodiment, wherein Ar is selected from the group consisting of:

12 12

pri čemu je svaki Ar opciono supstituisan na poziciji α, supstituentom izabranim iz grupe koju čine -NH2, -NH-C1-4alkil, -N(C1-4alkil)2, -NHR<10d>i -NR<10c>R<10d>; i pri čemu je Ar opciono supstituisan na drugoj poziciji halo supstituentom. wherein each Ar is optionally substituted in position α, with a substituent selected from the group consisting of -NH2, -NH-C1-4alkyl, -N(C1-4alkyl)2, -NHR<10d> and -NR<10c>R<10d>; and wherein Ar is optionally substituted at the second position with a halo substituent.

[0200] U jednom otelotvorenju, predmetni pronalazak se odnosi na ova jedinjenja formule (I) i njihove farmaceutski prihvatljive adicione soli i solvate, ili bilo koju njihovu podgrupu pomenutu u bilo kom drugom otelotvorenju, pri čemu Ar predstavlja 10-člani biciklični aromatični sistem prstenova koji se sastoji od dva kondenzovana 6-člana prstena, [0200] In one embodiment, the present invention relates to these compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof mentioned in any other embodiment, wherein Ar represents a 10-membered bicyclic aromatic ring system consisting of two fused 6-membered rings,

pri čemu je najmanje 1 atom ugljenika prstena B zamenjen atomom azota; pri čemu je opciono 1 dodatni atom ugljenika prstena A ili prstena B zamenjen atomom azota, pod uslovom da, kada atom azota zamenjuje jedan od dva kondenzovana atoma ugljenika, karbonilna grupa je prisutna u navedenom bicikličnom aromatičnom sistemu prstenova; pri čemu je svaki Ar opciono supstituisan prema bilo kom drugom otelotvorenju; naročito pri čemu je Ar opciono supstituisan jednim supstituentom kako je definisano u bilo kom drugom otelotvorenju. wherein at least 1 carbon atom of ring B is replaced by a nitrogen atom; wherein optionally 1 additional carbon atom of ring A or ring B is replaced by a nitrogen atom, provided that, when the nitrogen atom replaces one of the two fused carbon atoms, a carbonyl group is present in said bicyclic aromatic ring system; wherein each Ar is optionally substituted according to any other embodiment; particularly wherein Ar is optionally substituted with one substituent as defined in any other embodiment.

[0201] U jednom otelotvorenju, predmetni pronalazak se odnosi na ova jedinjenja formule (I) i njihove farmaceutski prihvatljive adicione soli i solvate, ili bilo koju njihovu podgrupu pomenutu u bilo kom drugom otelotvorenju, pri čemu je Ar opciono supstituisan jednim supstituentom kako je definisano u bilo kom drugom otelotvorenju. [0201] In one embodiment, the present invention relates to these compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof mentioned in any other embodiment, wherein Ar is optionally substituted with one substituent as defined in any other embodiment.

[0202] U jednom otelotvorenju, predmetni pronalazak se odnosi na ova jedinjenja formule (I) i njihove farmaceutski prihvatljive adicione soli i solvate, ili bilo koju njihovu podgrupu pomenutu u bilo kom drugom otelotvorenju, pri čemu je Ar opciono supstituisan sa jednim, dva, tri ili četiri supstituenta od kojih je svaki nezavisno izabran iz grupe koju čine halo, -OH, -NH2, -NH-C1-4alkil, -N(C1-4alkil)2, -NHR<10d>, -NR<10c>R<10d>, cijano, -CF3, -C(=O)-NH2, -C(=O)NH-C1-4alkil, -C(=O)-C1-4alkil, C1-4alkiloksi, -C(=O)-O-C1-4alkil, C2-6alkenil, C1-4alkil supstituisan jednim C1-4alkiloksi, i C1-4alkil opciono supstituisan jednim -NR<10a>R<10b>. [0202] In one embodiment, the present invention relates to these compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof mentioned in any other embodiment, wherein Ar is optionally substituted with one, two, three or four substituents each independently selected from the group consisting of halo, -OH, -NH2, -NH-C1-4alkyl, -N(C1-4alkyl)2, -NHR<10d>, -NR<10c>R<10d>, cyano, -CF3, -C(=O)-NH2, -C(=O)NH-C1-4alkyl, -C(=O)-C1-4alkyl, C1-4alkyloxy, -C(=O)-O-C1-4alkyl, C2-6alkenyl, C1-4alkyl substituted with one C1-4alkyloxy, and C1-4alkyl optionally substituted with one -NR<10a>R<10b>.

[0203] U jednom otelotvorenju, predmetni pronalazak se odnosi na ova jedinjenja formule (I) i njihove farmaceutski prihvatljive adicione soli i solvate, ili bilo koju njihovu podgrupu pomenutu u bilo kom drugom otelotvorenju, pri čemu Ar predstavlja [0203] In one embodiment, the present invention relates to these compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof mentioned in any other embodiment, wherein Ar represents

Ar je opciono supstituisan jednim supstituentom izabranim iz grupe koju čine halo, -OH, -NH2, -NH-C1-4alkil, -N(C1-4alkil)2, cijano i -CF3; konkretnije, Ar predstavlja Ar is optionally substituted with one substituent selected from the group consisting of halo, -OH, -NH2, -NH-C1-4alkyl, -N(C1-4alkyl)2, cyano and -CF3; more specifically, Ar represents

još konkretnije, Ar predstavlja more specifically, Ar represents

[0204] U jednom otelotvorenju, predmetni pronalazak se odnosi na ova jedinjenja formule (I) i njihove farmaceutski prihvatljive adicione soli i solvate, ili bilo koju njihovu podgrupu pomenutu u bilo kom drugom otelotvorenju, pri čemu Ar predstavlja [0204] In one embodiment, the present invention relates to these compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof mentioned in any other embodiment, wherein Ar represents

Ar je supstituisan jednim supstituentom izabranim iz grupe koju čine halo, -OH, - NH2, -NH-C1-4alkil, -N(C1-4alkil)2, cijano i -CF3; konkretnije, Ar predstavlja Ar is substituted with one substituent selected from the group consisting of halo, -OH, -NH2, -NH-C1-4alkyl, -N(C1-4alkyl)2, cyano and -CF3; more specifically, Ar represents

još konkretnije, Ar predstavlja more specifically, Ar represents

Het predstavlja (a-1); R<3a>predstavlja -NR<7a>R<7b>; i R<7a>i R<7b>predstavljaju vodonik. Het represents (a-1); R<3a>represents -NR<7a>R<7b>; and R<7a> and R<7b>represent hydrogen.

[0205] U jednom otelotvorenju, predmetni pronalazak se odnosi na ova jedinjenja formule (I) i njihove farmaceutski prihvatljive adicione soli i solvate, ili bilo koju njihovu podgrupu pomenutu u bilo kom drugom otelotvorenju, pri čemu su jedinjenja formule (I) ograničena na jedinjenja formule (I-a1): [0205] In one embodiment, the present invention relates to these compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof mentioned in any other embodiment, wherein compounds of formula (I) are limited to compounds of formula (I-a1):

[0206] Biće jasno da sve promenljive u strukturi formule (I-a1) mogu da se definišu prema definiciji za jedinjenja formule (I) ili bilo koje njihove podgrupe, kako je navedeno u bilo kom drugom otelotvorenju. [0206] It will be understood that all variables in the structure of formula (I-a1) may be defined as defined for the compounds of formula (I) or any subgroup thereof, as set forth in any other embodiment.

[0207] U jednom otelotvorenju, predmetni pronalazak se odnosi na ova jedinjenja formule (I) i njihove farmaceutski prihvatljive adicione soli i solvate, ili bilo koju njihovu podgrupu pomenutu u bilo kom drugom otelotvorenju, pri čemu su jedinjenja formule (I) ograničena na jedinjenja formule (I-a1): [0207] In one embodiment, the present invention relates to these compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof mentioned in any other embodiment, wherein compounds of formula (I) are limited to compounds of formula (I-a1):

12 12

pri čemu R<3a>predstavlja -NH2; i R<4a>predstavlja vodonik. wherein R<3a>represents -NH2; and R<4a>represents hydrogen.

[0208] U jednom otelotvorenju, predmetni pronalazak se odnosi na ova jedinjenja formule (I) i njihove farmaceutski prihvatljive adicione soli i solvate, ili bilo koju njihovu podgrupu pomenutu u bilo kom drugom otelotvorenju, pri čemu su jedinjenja formule (I) ograničena na jedinjenja formule (I-a1): [0208] In one embodiment, the present invention relates to these compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof mentioned in any other embodiment, wherein compounds of formula (I) are limited to compounds of formula (I-a1):

pri čemu R<3a>predstavlja -NH2; R<4a>predstavlja vodonik; i Ar predstavlja wherein R<3a>represents -NH2; R<4a>represents hydrogen; and Ar represents

konkretnije, Ar predstavlja more specifically, Ar represents

[0209] U jednom otelotvorenju, predmetni pronalazak se odnosi na ova jedinjenja formule (I) i njihove farmaceutski prihvatljive adicione soli i solvate, ili bilo koju njihovu podgrupu pomenutu u bilo kom drugom otelotvorenju, pri čemu su jedinjenja formule (I) ograničena na jedinjenja formule (I-a1): [0209] In one embodiment, the present invention relates to these compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof mentioned in any other embodiment, wherein compounds of formula (I) are limited to compounds of formula (I-a1):

pri čemu whereby

R<1>i R<2>predstavljaju vodonik; R<1> and R<2> represent hydrogen;

R<3a>predstavlja vodonik, -NR<7a>R<7b>, ili -OC1-4alkil; R<3a> represents hydrogen, -NR<7a>R<7b>, or -OC1-4alkyl;

R<4a>predstavlja vodonik; i R<4a>represents hydrogen; and

Ar predstavlja Ar represents

pri čemu je Ar supstituisan na poziciji označenoj sa α, supstituentom izabranim iz grupe koju čine -NH2, -NH-C1-4alkil, -N(C1-4alkil)2, -NHR<10d>, -NR<10c>R<10d>; i pri čemu je Ar opciono supstituisan na poziciji označenoj sa β, halo supstituentom; wherein Ar is substituted at the position indicated by α, with a substituent selected from the group consisting of -NH2, -NH-C1-4alkyl, -N(C1-4alkyl)2, -NHR<10d>, -NR<10c>R<10d>; and wherein Ar is optionally substituted at the position indicated by β, a halo substituent;

R<10c>i R<10d>svaki nezavisno predstavlja C1-4alkil supstituisan sa jednim, dva ili tri halo supstituenta; ili C1-4alkil supstituisan jednim C3-6cikloalkil supstituentom. R<10c> and R<10d> each independently represents C1-4 alkyl substituted with one, two or three halo substituents; or C1-4alkyl substituted with one C3-6cycloalkyl substituent.

[0210] U jednom otelotvorenju, predmetni pronalazak se bavi novim jedinjenjima formule (I-a1) [0210] In one embodiment, the present invention relates to novel compounds of formula (I-a1)

12 12

pri čemu whereby

R<1>i R<2>predstavljaju vodonik; R<1> and R<2> represent hydrogen;

R<3a>predstavlja vodonik, -NR<7a>R<7b>, ili -OC1-4alkil; R<3a> represents hydrogen, -NR<7a>R<7b>, or -OC1-4alkyl;

R<7a>predstavlja vodonik; R<7a> represents hydrogen;

R<7b>predstavlja vodonik ili C1-4alkil; R<7b>represents hydrogen or C1-4alkyl;

Z predstavlja -CH2CH2-; Z represents -CH2CH2-;

Y predstavlja -CH2- ili -CF2-; naročito -CH2-; Y represents -CH2- or -CF2-; especially -CH2-;

R<4a>predstavlja vodonik; i R<4a>represents hydrogen; and

Ar predstavlja Ar represents

pri čemu je Ar supstituisan na poziciji označenoj sa α, supstituentom izabranim iz grupe koju čine -NH2, -NH-C1-4alkil, -N(C1-4alkil)2, -NHR<10d>, -NR<10c>R<10d>; i pri čemu je Ar opciono supstituisan na poziciji označenoj sa β, halo supstituentom; wherein Ar is substituted at the position indicated by α, with a substituent selected from the group consisting of -NH2, -NH-C1-4alkyl, -N(C1-4alkyl)2, -NHR<10d>, -NR<10c>R<10d>; and wherein Ar is optionally substituted at the position indicated by β, a halo substituent;

R<10c>i R<10d>svaki nezavisno predstavlja C1-4alkil supstituisan sa jednim, dva ili tri halo supstituenta; ili C1-4alkil supstituisan jednim C3-6cikloalkil supstituentom; R<10c> and R<10d> each independently represents C1-4 alkyl substituted with one, two or three halo substituents; or C1-4alkyl substituted with one C3-6cycloalkyl substituent;

12 12

i njegovim farmaceutski prihvatljivim adicionim solima i solvatima. and pharmaceutically acceptable addition salts and solvates thereof.

[0211] U jednom otelotvorenju, predmetni pronalazak se bavi novim jedinjenjima formule (I-a1) [0211] In one embodiment, the present invention relates to novel compounds of formula (I-a1)

pri čemu whereby

R<1>i R<2>predstavljaju vodonik; R<1> and R<2> represent hydrogen;

R<3a>predstavlja vodonik, -NR<7a>R<7b>, ili -OC1-4alkil; R<3a> represents hydrogen, -NR<7a>R<7b>, or -OC1-4alkyl;

R<7a>predstavlja vodonik; R<7a> represents hydrogen;

R<7b>predstavlja vodonik ili C1-4alkil; R<7b>represents hydrogen or C1-4alkyl;

Z predstavlja -X-CR<5a>R<5b>- ili -CH2CH2-; Z represents -X-CR<5a>R<5b>- or -CH2CH2-;

R<5a>i R<5b>predstavljaju vodonik; X predstavlja -O-; R<5a> and R<5b> represent hydrogen; X represents -O-;

Y predstavlja -CH2- ili -CF2-; naročito -CH2-; Y represents -CH2- or -CF2-; especially -CH2-;

R<4a>predstavlja vodonik; i R<4a>represents hydrogen; and

Ar predstavlja Ar represents

12 12

pri čemu je Ar opciono supstituisan na poziciji označenoj sa α, supstituentom izabranim iz grupe koju čine -NH2, -NH-C1-4alkil, -N(C1-4alkil)2, -NHR<10d>, - NR<10c>R<10d>; i wherein Ar is optionally substituted at the position indicated by α, with a substituent selected from the group consisting of -NH2, -NH-C1-4alkyl, -N(C1-4alkyl)2, -NHR<10d>, -NR<10c>R<10d>; and

pri čemu je Ar opciono supstituisan na poziciji označenoj sa β, halo supstituentom; wherein Ar is optionally substituted at the position indicated by β, a halo substituent;

R<10c>i R<10d>svaki nezavisno predstavlja C1-4alkil supstituisan sa jednim, dva ili tri halo supstituenta; ili C1-4alkil supstituisan jednim C3-6cikloalkil supstituentom; R<10c> and R<10d> each independently represents C1-4 alkyl substituted with one, two or three halo substituents; or C1-4alkyl substituted with one C3-6cycloalkyl substituent;

i njegovim farmaceutski prihvatljivim adicionim solima i solvatima. and pharmaceutically acceptable addition salts and solvates thereof.

[0212] U jednom otelotvorenju, predmetni pronalazak se bavi novim jedinjenjima formule (I-a1) [0212] In one embodiment, the present invention relates to novel compounds of formula (I-a1)

pri čemu whereby

R<1>i R<2>predstavljaju vodonik; R<1> and R<2> represent hydrogen;

R<3a>predstavlja -NR<7a>R<7b>; R<3a>represents -NR<7a>R<7b>;

R<7a>predstavlja vodonik; R<7a> represents hydrogen;

R<7b>predstavlja vodonik; R<7b>represents hydrogen;

Z predstavlja -X-CR<5a>R<5b>- ili -CH2CH2-; Z represents -X-CR<5a>R<5b>- or -CH2CH2-;

R<5a>i R<5b>predstavljaju vodonik; X predstavlja -O-; R<5a> and R<5b> represent hydrogen; X represents -O-;

Y predstavlja -CH2-; Y represents -CH2-;

12 12

R<4a>predstavlja vodonik; i R<4a>represents hydrogen; and

Ar predstavlja Ar represents

pri čemu je Ar opciono supstituisan na poziciji označenoj sa α, sa -NH2; i pri čemu je Ar supstituisan na poziciji označenoj sa β, halo supstituentom, naročito Br; wherein Ar is optionally substituted at the position indicated by α, with -NH2; and wherein Ar is substituted at the position indicated by β, a halo substituent, especially Br;

i njegovim farmaceutski prihvatljivim adicionim solima i solvatima. and pharmaceutically acceptable addition salts and solvates thereof.

[0213] U jednom otelotvorenju, predmetni pronalazak se odnosi na ova jedinjenja formule (I) i njihove farmaceutski prihvatljive adicione soli i solvate, ili bilo koju njihovu podgrupu pomenutu u bilo kom drugom otelotvorenju, pri čemu [0213] In one embodiment, the present invention relates to these compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof mentioned in any other embodiment, wherein

Z predstavlja -X-CR<5a>R<5b>- ili -CH2CH2-. Z represents -X-CR<5a>R<5b>- or -CH2CH2-.

[0214] U jednom otelotvorenju, predmetni pronalazak se odnosi na ova jedinjenja formule (I) i njihove farmaceutski prihvatljive adicione soli i solvate, ili bilo koju njihovu podgrupu pomenutu u bilo kom drugom otelotvorenju, pri čemu [0214] In one embodiment, the present invention relates to these compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof mentioned in any other embodiment, wherein

Z predstavlja -X-CR<5a>R<5b>- ili -CH2CH2-; Z represents -X-CR<5a>R<5b>- or -CH2CH2-;

R<5a>i R<5b>predstavljaju vodonik; R<5a> and R<5b> represent hydrogen;

X predstavlja -O-. X represents -O-.

[0215] U jednom otelotvorenju, predmetni pronalazak se odnosi na ova jedinjenja formule (I) i njihove farmaceutski prihvatljive adicione soli i solvate, ili bilo koju njihovu podgrupu pomenutu u bilo kom drugom otelotvorenju, pri čemu [0215] In one embodiment, the present invention relates to these compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof mentioned in any other embodiment, wherein

12 12

Z predstavlja -X-CR<5a>R<5b>- ili -CH2CH2-; Z represents -X-CR<5a>R<5b>- or -CH2CH2-;

R<5a>i R<5b>predstavljaju vodonik; R<5a> and R<5b> represent hydrogen;

X predstavlja -O-; X represents -O-;

Het predstavlja (a-1). Het represents (a-1).

[0216] U jednom otelotvorenju, predmetni pronalazak se odnosi na ova jedinjenja formule (I) i njihove farmaceutski prihvatljive adicione soli i solvate, ili bilo koju njihovu podgrupu pomenutu u bilo kom drugom otelotvorenju, pri čemu [0216] In one embodiment, the present invention relates to these compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof mentioned in any other embodiment, wherein

Z predstavlja -X-CR<5a>R<5b>- ili -CH2CH2-; Z represents -X-CR<5a>R<5b>- or -CH2CH2-;

R<5a>i R<5b>predstavljaju vodonik; R<5a> and R<5b> represent hydrogen;

X predstavlja -O-; X represents -O-;

Het predstavlja (a-1); Het represents (a-1);

R<3a>predstavlja -NR<7a>R<7b>; R<3a>represents -NR<7a>R<7b>;

R<7a>predstavlja vodonik; R<7a> represents hydrogen;

R<7b>predstavlja vodonik. R<7b>represents hydrogen.

[0217] U jednom otelotvorenju, predmetni pronalazak se odnosi na ova jedinjenja formule (I) i njihove farmaceutski prihvatljive adicione soli i solvate, ili bilo koju njihovu podgrupu pomenutu u bilo kom drugom otelotvorenju, pri čemu X predstavlja -O-. [0217] In one embodiment, the present invention relates to these compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof mentioned in any other embodiment, wherein X represents -O-.

[0218] U jednom otelotvorenju, predmetni pronalazak se odnosi na ova jedinjenja formule (I) i njihove farmaceutski prihvatljive adicione soli i solvate, ili bilo koju njihovu podgrupu pomenutu u bilo kom drugom otelotvorenju, pri čemu [0218] In one embodiment, the present invention relates to these compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof mentioned in any other embodiment, wherein

1 1

Z predstavlja -X-CR<5a>R<5b>- ili -CH2CH2-; Z represents -X-CR<5a>R<5b>- or -CH2CH2-;

R<5a>i R<5b>predstavljaju vodonik; R<5a> and R<5b> represent hydrogen;

X predstavlja -O-; X represents -O-;

Ar predstavlja Ar represents

pri čemu je Ar opciono supstituisan na poziciji označenoj sa α, supstituentom izabranim iz grupe koju čine -NH2, -NH-C1-4alkil i -NHR<10d>; i pri čemu je Ar opciono supstituisan na poziciji označenoj sa β, supstituentom izabranim iz grupe koju čine halo i CF3; wherein Ar is optionally substituted at the position indicated by α, with a substituent selected from the group consisting of -NH2, -NH-C1-4alkyl and -NHR<10d>; and wherein Ar is optionally substituted at the position indicated by β with a substituent selected from the group consisting of halo and CF 3 ;

pod uslovom da je Ar supstituisan na najmanje jednoj od pozicija označenih sa α ili β; provided that Ar is substituted in at least one of the positions indicated by α or β;

Het predstavlja (a-1); Het represents (a-1);

R<3a>predstavlja -NR<7a>R<7b>; R<3a>represents -NR<7a>R<7b>;

R<7a>predstavlja vodonik; R<7a> represents hydrogen;

R<7b>predstavlja vodonik. R<7b>represents hydrogen.

[0219] U jednom otelotvorenju, predmetni pronalazak se odnosi na ova jedinjenja formule (I) i njihove farmaceutski prihvatljive adicione soli i solvate, ili bilo koju njihovu podgrupu pomenutu u bilo kom drugom otelotvorenju, pri čemu [0219] In one embodiment, the present invention relates to these compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof mentioned in any other embodiment, wherein

Het predstavlja (a-1); Het represents (a-1);

R<3a>predstavlja -NR<7a>R<7b>; R<3a>represents -NR<7a>R<7b>;

1 1 1 1

R<7a>predstavlja vodonik; R<7a> represents hydrogen;

R<7b>predstavlja vodonik. R<7b>represents hydrogen.

[0220] U jednom otelotvorenju, predmetni pronalazak se odnosi na ova jedinjenja formule (I) i njihove farmaceutski prihvatljive adicione soli i solvate, ili bilo koju njihovu podgrupu pomenutu u bilo kom drugom otelotvorenju, pri čemu [0220] In one embodiment, the present invention relates to these compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof mentioned in any other embodiment, wherein

R<3a>, R<3b>, R<3c>, R<3d>i R<3e>predstavljaju -NR<7a>R<7b>; R<3a>, R<3b>, R<3c>, R<3d> and R<3e> represent -NR<7a>R<7b>;

R<7a>predstavlja vodonik; R<7a> represents hydrogen;

R<7b>predstavlja vodonik, C3-6cikloalkil, ili C1-4alkil. R<7b>represents hydrogen, C3-6cycloalkyl, or C1-4alkyl.

[0221] U jednom otelotvorenju, predmetni pronalazak se odnosi na ova jedinjenja formule (I) i njihove farmaceutski prihvatljive adicione soli i solvate, ili bilo koju njihovu podgrupu pomenutu u bilo kom drugom otelotvorenju, pri čemu [0221] In one embodiment, the present invention relates to these compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof mentioned in any other embodiment, wherein

R<3a>, R<3b>, R<3c>, R<3d>i R<3e>predstavljaju -NR<7a>R<7b>; R<3a>, R<3b>, R<3c>, R<3d> and R<3e> represent -NR<7a>R<7b>;

R<7a>predstavlja vodonik; R<7a> represents hydrogen;

R<7b>predstavlja vodonik. R<7b>represents hydrogen.

[0222] U jednom otelotvorenju, predmetni pronalazak se odnosi na ova jedinjenja formule (I) i njihove farmaceutski prihvatljive adicione soli i solvate, ili bilo koju njihovu podgrupu pomenutu u bilo kom drugom otelotvorenju, pri čemu R<11>predstavlja vodonik, C1-4alkil, ili C1-[0222] In one embodiment, the present invention relates to these compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof mentioned in any other embodiment, wherein R<11> represents hydrogen, C1-4alkyl, or C1-

4alkil supstituisan jednim supstituentom izabranim iz grupe koju čine -OH, -O-C1-4alkil, -NH2, -NH-C1-4alkil i -N(C1-4alkil)2; i 4alkyl substituted with one substituent selected from the group consisting of -OH, -O-C1-4alkyl, -NH2, -NH-C1-4alkyl and -N(C1-4alkyl)2; and

R<10c>i R<10d>svaki nezavisno predstavlja C3-6cikloalkil; R<14>; C3-6cikloalkil supstituisan sa jednim, dva ili tri supstituenta od kojih je svaki nezavisno izabran iz grupe koju čine halo, -OH i -O-C1-4alkil; C1-4alkil supstituisan sa jednim, dva ili tri supstituenta od kojih je svaki nezavisno R<10c> and R<10d> each independently represents C3-6cycloalkyl; R<14>; C3-6cycloalkyl substituted with one, two or three substituents each independently selected from the group consisting of halo, -OH and -O-C1-4alkyl; C 1-4 alkyl substituted with one, two or three substituents, each of which is independent

1 2 1 2

izabran iz grupe koju čine halo, -OH i -O-C1-4alkil; ili C1-4alkil supstituisan jednim supstituentom izabranim iz grupe koju čine C3-6cikloalkil i R<14>. selected from the group consisting of halo, -OH and -O-C1-4alkyl; or C1-4alkyl substituted with one substituent selected from the group consisting of C3-6cycloalkyl and R<14>.

[0223] U jednom otelotvorenju, predmetni pronalazak se odnosi na ova jedinjenja formule (I) i njihove farmaceutski prihvatljive adicione soli i solvate, ili bilo koju njihovu podgrupu pomenutu u bilo kom drugom otelotvorenju, pri čemu Y predstavlja -CH2-; i Z predstavlja -CH2CH2-. [0223] In one embodiment, the present invention relates to these compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof mentioned in any other embodiment, wherein Y represents -CH2-; and Z represents -CH2CH2-.

[0224] U jednom otelotvorenju, predmetni pronalazak se odnosi na podgrupu formule (I) kako je definisana u opštim reakcionim šemama. [0224] In one embodiment, the present invention relates to a subgroup of formula (I) as defined in general reaction schemes.

[0225] U jednom otelotvorenju, jedinjenje formule (I) izabrano je iz grupe koja se sastoji od jedinjenja 2 i 58. [0225] In one embodiment, the compound of formula (I) is selected from the group consisting of compounds 2 and 58.

[0226] U jednom otelotvorenju, jedinjenje formule (I) izabrano je iz grupe koja se sastoji od jedinjenja 2 i 80. [0226] In one embodiment, the compound of formula (I) is selected from the group consisting of compounds 2 and 80.

[0227] U jednom otelotvorenju, jedinjenje formule (I) izabrano je iz grupe koja se sastoji od jedinjenja 74, 75, 76, 77, 78, 79, 80 i 81. [0227] In one embodiment, the compound of formula (I) is selected from the group consisting of compounds 74, 75, 76, 77, 78, 79, 80 and 81.

[0228] U jednom otelotvorenju, jedinjenje formule (I) izabrano je iz grupe koja se sastoji od jedinjenja 2, 58, 74, 75, 76, 77, 78, 79, 80, 81, 154, 159, 235, 240 i 247. [0228] In one embodiment, the compound of formula (I) is selected from the group consisting of compounds 2, 58, 74, 75, 76, 77, 78, 79, 80, 81, 154, 159, 235, 240 and 247.

[0229] U jednom otelotvorenju, jedinjenje formule (I) izabrano je iz grupe koja se sastoji od jedinjenja 2 i 58, [0229] In one embodiment, the compound of formula (I) is selected from the group consisting of compounds 2 and 58,

i njegovim farmaceutski prihvatljivim adicionim solima i solvatima. and pharmaceutically acceptable addition salts and solvates thereof.

[0230] U jednom otelotvorenju, jedinjenje formule (I) izabrano je iz grupe koja se sastoji od jedinjenja 2 i 80, [0230] In one embodiment, the compound of formula (I) is selected from the group consisting of compounds 2 and 80,

i njegovim farmaceutski prihvatljivim adicionim solima i solvatima. and pharmaceutically acceptable addition salts and solvates thereof.

1 1

[0231] U jednom otelotvorenju, jedinjenje formule (I) izabrano je iz grupe koja se sastoji od jedinjenja 74, 75, 76, 77, 78, 79, 80 i 81, [0231] In one embodiment, the compound of formula (I) is selected from the group consisting of compounds 74, 75, 76, 77, 78, 79, 80 and 81,

i njegovim farmaceutski prihvatljivim adicionim solima i solvatima. and pharmaceutically acceptable addition salts and solvates thereof.

[0232] U jednom otelotvorenju, jedinjenje formule (I) izabrano je iz grupe koja se sastoji od jedinjenja 2, 58, 74, 75, 76, 77, 78, 79, 80, 81, 154, 159, 235, 240 i 247 [0232] In one embodiment, the compound of formula (I) is selected from the group consisting of compounds 2, 58, 74, 75, 76, 77, 78, 79, 80, 81, 154, 159, 235, 240 and 247

i njegovim farmaceutski prihvatljivim adicionim solima i solvatima. and pharmaceutically acceptable addition salts and solvates thereof.

[0233] U jednom otelotvorenju, jedinjenje formule (I) izabrano je iz grupe koja se sastoji od bilo kojih prikazanih jedinjenja, [0233] In one embodiment, the compound of formula (I) is selected from the group consisting of any of the compounds shown,

i njihovih slobodnih baza, farmaceutski prihvatljivih adicionih soli i solvata. and their free bases, pharmaceutically acceptable addition salts and solvates.

[0234] Smatra se da su sve moguće kombinacije prethodno naznačenih jedinjenja obuhvaćene opsegom pronalaska. [0234] All possible combinations of the aforementioned compounds are considered to be within the scope of the invention.

Postupci pripreme Preparation procedures

[0235] U ovom odeljku, kao i u svim drugim odeljcima, osim ako kontekst ne nalaže drugačije, reference na formulu (I) takođe uključuju sve njene druge podgrupe i primere kako su ovde definisani. [0235] In this section, as in all other sections, unless the context otherwise dictates, references to formula (I) also include all other subgroups and examples thereof as defined herein.

[0236] Opšta priprema nekih uobičajenih primera jedinjenja formule (I) opisana je u nastavku ovog teksta i u specifičnim primerima, i oni se uopšteno pripremaju od polaznih supstanci koje su komercijalno dostupne ili se pripremaju standardnim sintetičkim postupcima koje stručnjaci uobičajeno koriste. Sledeće šeme treba samo da predstavljaju primere pronalaska, i ni na koji način ih ne treba tumačiti kao ograničenje pronalaska. [0236] The general preparation of some common examples of compounds of formula (I) is described below in the specific examples, and these are generally prepared from starting materials that are commercially available or are prepared by standard synthetic procedures commonly used by those skilled in the art. The following schematics are intended to be illustrative of the invention only, and should in no way be construed as limiting the invention.

[0237] Alternativno, jedinjenja iz predmetnog pronalaska takođe mogu da se pripreme analognim reakcionim protokolima kao što je opisano u opštim šemama u nastavku, u kombinaciji sa standardnim sintetičkim postupcima koje uobičajeno koriste stručnjaci u oblasti organske hemije. [0237] Alternatively, the compounds of the present invention may also be prepared by analogous reaction protocols as described in the general schemes below, in combination with standard synthetic procedures commonly used by those skilled in the art of organic chemistry.

1 4 1 4

[0238] Stručnjaku će biti jasno da u reakcijama koje su opisane u šemama može biti neophodno da se zaštite reakcione funkcionalne grupe, na primer, hidroksi, amino ili karboksi grupa, kada su one poželjne u krajnjem proizvodu, kako bi se izbeglo njihovo neželjeno učešće u reakciji. Uobičajene zaštitne grupe mogu da se koriste u skladu sa standardnom praksom. To je ilustrovano u specifičnim primerima. [0238] It will be clear to one of skill in the art that in the reactions described in the schemes it may be necessary to protect reactive functional groups, for example, hydroxy, amino or carboxy groups, when these are desired in the final product, in order to avoid their undesired participation in the reaction. Common protecting groups can be used according to standard practice. This is illustrated in specific examples.

[0239] Stručnjaku će biti jasno da za reakcije opisane u šemama može biti preporučljivo ili neophodno da se reakcija obavi u inertnoj atmosferi, kao, na primer, u atmosferi gasovitog N2, na primer, kada se NaH koristi u reakciji. [0239] One skilled in the art will appreciate that for the reactions described in the schemes it may be advisable or necessary to carry out the reaction in an inert atmosphere, such as, for example, in an atmosphere of gaseous N 2 , for example, when NaH is used in the reaction.

[0240] Stručnjaku će biti očito da može biti neophodno da se reakciona smeša ohladi pre obrade reakcije (odnosi se na niz procesa koji su potrebni da za izolovanje i prečišćavanje proizvoda hemijske reakcije, kao što je, na primer, prekidanje reakcije, hromatografija na koloni, ekstrakcija). [0240] It will be apparent to one skilled in the art that it may be necessary to cool the reaction mixture prior to reaction workup (referring to a series of processes required to isolate and purify the products of a chemical reaction, such as, for example, quenching, column chromatography, extraction).

[0241] Stručnjaku će biti jasno da zagrevanje reakcione smeše uz mešanje može poboljšati ishod reakcije. U nekim reakcijama, zagrevanje u mikrotalasnoj pećnici može da se koristi umesto uobičajenog zagrevanja kako bi se smanjilo ukupno trajanje reakcije. [0241] One skilled in the art will appreciate that heating the reaction mixture while stirring can improve the outcome of the reaction. In some reactions, microwave heating can be used instead of conventional heating to reduce the overall reaction time.

[0242] Stručnjaku će biti jasno da druga sekvenca hemijskih reakcija prikazanih u šemama u nastavku može takođe dati željeno jedinjenje formule (I). [0242] It will be clear to one skilled in the art that another sequence of chemical reactions shown in the schemes below can also provide the desired compound of formula (I).

[0243] Stručnjaku će biti jasno da intermedijeri i jedinjenja prikazani u šemama u nastavku mogu dalje da se koriste u skladu sa postupcima koji su dobro poznati stručnjaku. [0243] It will be clear to one skilled in the art that the intermediates and compounds shown in the schemes below can be further used according to procedures well known to those skilled in the art.

[0244] Stručnjaku će biti jasno da više jedinjenja formule (I) može da se pripremi koristeći slične sintetičke protokole, kao što je opisano u šemama u nastavku. [0244] One skilled in the art will appreciate that multiple compounds of formula (I) can be prepared using similar synthetic protocols, as described in the schemes below.

[0245] U slučaju da je jedna od polaznih supstanci dostupna u obliku soli, stručnjaku će biti jasno da može biti neophodno da se so prvo tretira bazom, kao što je, na primer, N,N-diizopropiletilamin (DIPEA). [0245] In case one of the starting substances is available in the form of a salt, it will be clear to the person skilled in the art that it may be necessary to first treat the salt with a base, such as, for example, N,N-diisopropylethylamine (DIPEA).

1 1

[0246] Sve promenljive su definisane kao što je prethodno navedeno, osim ako nije drugačije naznačeno ili jasno iz konteksta. [0246] All variables are defined as above, unless otherwise indicated or clear from the context.

[0247] Stručnjaku će biti jasno da hemijski postupci analogni onima koji su opisani u šemama 1 do 9 takođe mogu da se primene za dobijanje jedinjenja formule (I), pri čemu Het predstavlja biciklični aromatični heterociklični sistem prstenova (a-4) ili (a-5). Neki tipični primeri su ilustrovani u specifičnim primerima. Pored toga, ove informacije mogu da se kombinuju sa standardnim sintetičkim postupcima koje uobičajeno koriste stručnjaci za oblast organske hemije, radi dobijanja više jedinjenja formule (I), pri čemu Het predstavlja (a-4) ili (a-5). [0247] It will be clear to the person skilled in the art that chemical procedures analogous to those described in Schemes 1 to 9 can also be applied to obtain compounds of formula (I), wherein Het represents a bicyclic aromatic heterocyclic ring system (a-4) or (a-5). Some typical examples are illustrated in specific examples. In addition, this information can be combined with standard synthetic procedures commonly used by those skilled in the art of organic chemistry to obtain multiple compounds of formula (I) wherein Het is (a-4) or (a-5).

[0248] Uopšteno, jedinjenja formule (I) mogu da se pripreme prema šemi 1: [0248] In general, compounds of formula (I) can be prepared according to scheme 1:

[0249] U šemi 1, „LG1“ je definisan kao odgovarajuća odlazeća grupa kao što je, na primer, halogen; „LG2“ je definisan kao odgovarajuća odlazeća grupa kao što je, na primer, halogen ili -SCH3. „LG3“ je definisan kao odlazeća grupa kao što je halogen i -SCH3. Sve druge promenljive u šemi 1 definisane su u skladu sa opsegom predmetnog pronalaska. [0249] In Scheme 1, "LG1" is defined as a suitable leaving group such as, for example, halogen; "LG2" is defined as a suitable leaving group such as, for example, halogen or -SCH3. "LG3" is defined as a leaving group such as halogen and -SCH3. All other variables in Scheme 1 are defined within the scope of the present invention.

[0250] U šemi 1 obično važe sledeći reakcioni uslovi: [0250] In Scheme 1, the following reaction conditions usually apply:

1: Različiti skupovi reakcionih uslova u zavisnosti od definicije R<3a>, R<3b>ili R<3c>: 1: Different sets of reaction conditions depending on the definition of R<3a>, R<3b> or R<3c>:

1 1

1a: Kada je R<3a>, R<3b>ili R<3c>halogen, korak 1 može da se preskoči. 1a: When R<3a>, R<3b>or R<3c>is halogen, step 1 can be skipped.

1b: Kada je R<3a>, R<3b>ili R<3c>NR<7a>R<7b>, u prisustvu odgovarajućeg amina formule HNR<7a>R<7b>, sa odgovarajućim rastvaračem kao što je, na primer, H2O, MeOH, ili EtOH, na odgovarajućoj temperaturi kao što je, na primer, 100-130°C, obično u uslovima mikrotalasne pećnice ili koristeći autoklav za zagrevanje. 1b: When R<3a>, R<3b>or R<3c>NR<7a>R<7b>, in the presence of a suitable amine of the formula HNR<7a>R<7b>, with a suitable solvent such as, for example, H2O, MeOH, or EtOH, at a suitable temperature such as, for example, 100-130°C, usually under microwave conditions or using an autoclave for heating.

1c: Kada je R<3a>, R<3b>ili R<3c>-O-C1-4alkil, u prisustvu odgovarajućeg HO-C1-4alkila, sa odgovarajućom bazom kao što je, na primer, NaH, kalijum terc-butoksid (tBuOK) u odgovarajućem rastvaraču kao što je, na primer, tetrahidrofuran (THF) na odgovarajućoj temperaturi. 1c: When R<3a>, R<3b>or R<3c> is -O-C1-4alkyl, in the presence of a suitable HO-C1-4alkyl, with a suitable base such as, for example, NaH, potassium tert-butoxide (tBuOK) in a suitable solvent such as, for example, tetrahydrofuran (THF) at a suitable temperature.

Alternativno u prisustvu odgovarajućeg HO-C1-4alkila kao rastvarača sa odgovarajućom kiselinom, kao što je, na primer, HCl. Alternatively in the presence of the appropriate HO-C 1-4 alkyl as solvent with a suitable acid such as, for example, HCl.

1d: Kada je R<3a>, R<3b>ili R<3c>vodonik, u uslovima hidrogenovanja: pod atmosferom gasovitog H2u prisustvu katalizatora kao što je, na primer, Reni Ni, Pd/C (na primer, 5 mas.% ili 10 mas.%) ili Pt/C (na primer, 5 mas.%) u odgovarajućem rastvaraču kao što je, na primer, metanol (MeOH), etanol (EtOH) ili THF; 1d: When R<3a>, R<3b>or R<3c> is hydrogen, under hydrogenation conditions: under an atmosphere of gaseous H2 in the presence of a catalyst such as, for example, Raney Ni, Pd/C (for example, 5 wt.% or 10 wt.%) or Pt/C (for example, 5 wt.%) in a suitable solvent such as, for example, methanol (MeOH), ethanol (EtOH) or THF;

1e: Kada je R<3a>, R<3b>ili R<3c>C1-4alkil, u prisustvu odgovarajuće boronske kiseline ili estra kao što je, na primer, metil boronska kiselina sa odgovarajućim katalizatorom kao što je, na primer, 1,1'-bis(difenilfosfino)ferocen i sa odgovarajućom bazom kao što je, na primer, K3PO4u odgovarajućoj smeši rastvarača kao što je, na primer, dioksan/H2O u odnosu 5 prema 1 na odgovarajućoj temperaturi, kao što je, na primer, 100°C; 1e: When R<3a>, R<3b>or R<3c> is C1-4alkyl, in the presence of a suitable boronic acid or ester such as, for example, methyl boronic acid with a suitable catalyst such as, for example, 1,1'-bis(diphenylphosphino)ferrocene and with a suitable base such as, for example, K3PO4 in a suitable solvent mixture such as, for example, dioxane/H2O in a ratio of 5 1 at a suitable temperature, such as, for example, 100°C;

2: u prisustvu odgovarajuće kiseline, kao što je, na primer, 4 M HCl u dioksanu ili 4 M HCl u MeOH, sa odgovarajućim rastvaračem kao što je, na primer, MeOH, na odgovarajućoj temperaturi kao što je, na primer, sobna temperatura; ili, alternativno, u prisustvu odgovarajuće kiseline kao što je, na primer, trifluorsirćetna kiselina (TFA) u dihlormetanu (DCM) na odgovarajućoj temperaturi, ili sirćetna kiselina u THF i vodi na odgovarajućoj temperaturi, kao što je, na primer, sobna temperatura. 2: in the presence of a suitable acid, such as, for example, 4 M HCl in dioxane or 4 M HCl in MeOH, with a suitable solvent such as, for example, MeOH, at a suitable temperature such as, for example, room temperature; or, alternatively, in the presence of an appropriate acid such as, for example, trifluoroacetic acid (TFA) in dichloromethane (DCM) at an appropriate temperature, or acetic acid in THF and water at an appropriate temperature, such as, for example, room temperature.

1 1

3: u prisustvu odgovarajućeg anhidrida kiseline formule (C1-4alkilC=O)2O sa odgovarajućim rastvaračem kao što je piridin na odgovarajućoj temperaturi. Kada je R<3a>, R<3b>ili R<3c>NH2, (C1-4alkilC=O)2O može da reaguje sa NH2radi dobijanja intermedijera N(C1-4alkilC=O)2. Takav intermedijer može da se konvertuje u ciljni proizvod u odgovarajućem rastvaraču kao što je, na primer, MeOH na odgovarajućoj temperaturi kao što je, na primer, 100-130°C u mikrotalasnoj pećnici ili koristeći autoklav za zagrevanje. Za reakciju može biti korisno prisustvo kiseline, kao što je HCl ili C1-4alkilCO2H. 3: in the presence of an appropriate acid anhydride of the formula (C1-4alkylC=O)2O with an appropriate solvent such as pyridine at an appropriate temperature. When R<3a>, R<3b>or R<3c> is NH2, (C1-4alkylC=O)2O can react with NH2 to give the intermediate N(C1-4alkylC=O)2. Such an intermediate can be converted to the target product in a suitable solvent such as, for example, MeOH at a suitable temperature such as, for example, 100-130°C in a microwave oven or using an autoclave for heating. The presence of an acid, such as HCl or C1-4alkylCO2H, may be beneficial for the reaction.

[0251] Polazne supstance u šemi 1 su komercijalno dostupne ili mogu da se pripreme na standardni način koji je očigledan stručnjacima, ili kao što je opisano u sledećim opštim šemama. [0251] The starting substances in Scheme 1 are commercially available or can be prepared in a standard manner apparent to those skilled in the art, or as described in the following general schemes.

Opšta šema 2a General scheme 2a

[0252] Uopšteno, intermedijeri formule III, V i VII, gde Z predstavlja -O-CHR<5a>-, mogu da se pripreme prema šemi 2a. Sve druge promenljive u šemi 2a su definisane u skladu sa opsegom predmetnog pronalaska. Stručnjaku će biti jasno da je pogodna zaštitna grupa potrebna kada je R<3a>, R<3b>ili R<3c>-NH2ili -NHR<7b>; [0252] In general, intermediates of formula III, V and VII, where Z represents -O-CHR<5a>-, can be prepared according to scheme 2a. All other variables in Scheme 2a are defined within the scope of the present invention. One skilled in the art will appreciate that a suitable protecting group is required when R<3a>, R<3b> or R<3c> is -NH2 or -NHR<7b>;

1 1

[0253] U šemi 2a važe sledeći reakcioni uslovi: [0253] In Scheme 2a, the following reaction conditions apply:

1: Micunobuova reakcija: 1: Mitsunobu's reaction:

1a: U prisustvu PPh3sa polimernom podlogom, diizopropil azodikarboksilata (DIAD) ili dietil azodikarboksilata (DEAD) ili Bis(1,1-dimetiletil)-azodikarboksilata (DBAD) u odgovarajućem rastvaraču kao što je, na primer, anhidrovani THF, na odgovarajućoj temperaturi kao što je, na primer, sobna temperatura. 1a: In the presence of PPh3 with polymer support, diisopropyl azodicarboxylate (DIAD) or diethyl azodicarboxylate (DEAD) or Bis(1,1-dimethylethyl)-azodicarboxylate (DBAD) in a suitable solvent such as, for example, anhydrous THF, at a suitable temperature such as, for example, room temperature.

1b: U prisustvu trifenilfosfina (PPh3), DIAD ili DEAD u odgovarajućem rastvaraču kao što je, na primer, anhidrovani THF, na odgovarajućoj temperaturi kao što je, na primer, sobna temperatura. 1b: In the presence of triphenylphosphine (PPh3), DIAD or DEAD in a suitable solvent such as, for example, anhydrous THF, at a suitable temperature such as, for example, room temperature.

1c: U prisustvu cijanometilen tributilfosforana (CMBP) ili cijanometilen trimetilfosforana (CMMP), u odgovarajućem rastvaraču kao što je, na primer, anhidrovani toluen, na odgovarajućoj temperaturi kao što je, na primer, 80°C. 1c: In the presence of cyanomethylene tributylphosphorane (CMBP) or cyanomethylene trimethylphosphorane (CMMP), in a suitable solvent such as, for example, anhydrous toluene, at a suitable temperature such as, for example, 80°C.

1 1

[0254] Polazne supstance u šemi 2a su komercijalno dostupne, ili mogu da se pripreme na standardni način koji je očigledan stručnjacima, ili kao što je opisano u sledećim opštim šemama. Stručnjaku će biti jasno da, kada je R<5a>C1-4alkil, različiti izomeri mogu međusobno da se razdvoje koristeći reversno faznu tečnu hromatografiju visokih performansi (RP-HPLC) ili superkritičnu tečnu hromatografiju (SFC). [0254] The starting substances in Scheme 2a are commercially available, or can be prepared in a standard manner apparent to those skilled in the art, or as described in the following general schemes. One skilled in the art will appreciate that, when R<5a>C1-4alkyl, the different isomers can be separated from each other using reverse phase high performance liquid chromatography (RP-HPLC) or supercritical liquid chromatography (SFC).

Opšta šema 2b General scheme 2b

[0255] Intermedijeri formule II, IV i VI, gde Z predstavlja -X<a>-CHR<5a>-, mogu da se pripreme prema šemi 2b. U šemi 2b, „X<a>“ je definisan kao O ili S; „LG“ je definisan kao odlazeća grupa kao što je, na primer, halogen, mezilat (MsO) i tozilat (TosO), poželjno TosO. „LG1“ je definisan kao odlazeća grupa kao što je, na primer, halogen; „LG2“ je definisan kao odlazeća grupa kao što je, na primer, halogen ili -SCH3. „LG3“ je definisan kao odlazeća grupa kao što je, na primer, halogen ili -SCH3. Sve druge promenljive u šemi 2b su definisane u skladu sa opsegom predmetnog pronalaska. [0255] Intermediates of formula II, IV and VI, where Z represents -X<a>-CHR<5a>-, can be prepared according to scheme 2b. In Scheme 2b, "X<a>" is defined as O or S; "LG" is defined as a leaving group such as, for example, halogen, mesylate (MsO) and tosylate (TosO), preferably TosO. "LG1" is defined as a leaving group such as, for example, halogen; "LG2" is defined as a leaving group such as, for example, halogen or -SCH3. "LG3" is defined as a leaving group such as, for example, halogen or -SCH3. All other variables in Scheme 2b are defined within the scope of the present invention.

[0256] U šemi 2b važe sledeći reakcioni uslovi: [0256] In Scheme 2b, the following reaction conditions apply:

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1: u prisustvu baze kao što je, na primer, K2CO3, trietilamin (Et3N) ili DIPEA, u odgovarajućem rastvaraču kao što je CH3CN, DCM ili N,N-dimetilacetamid (DMA). 1: in the presence of a base such as, for example, K2CO3, triethylamine (Et3N) or DIPEA, in a suitable solvent such as CH3CN, DCM or N,N-dimethylacetamide (DMA).

[0257] Polazne supstance u šemi 2b su komercijalno dostupne, ili mogu da se pripreme na standardni način koji je očigledan stručnjacima, ili kao što je opisano u sledećim opštim šemama. Stručnjaku će biti jasno da, kada je R<5a>C1-4alkil, različiti izomeri mogu međusobno da se razdvoje koristeći reversno faznu tečnu hromatografiju visokih performansi (RP-HPLC) ili superkritičnu tečnu hromatografiju (SFC). [0257] The starting substances in Scheme 2b are commercially available, or can be prepared in a standard manner apparent to those skilled in the art, or as described in the following general schemes. One skilled in the art will appreciate that, when R<5a>C1-4alkyl, the different isomers can be separated from each other using reverse phase high performance liquid chromatography (RP-HPLC) or supercritical liquid chromatography (SFC).

Opšta šema 2c General scheme 2c

[0258] Intermedijeri III, V i VII, gde Z predstavlja -X<a>-CHR<5a>-, mogu da se pripreme prema šemi 2c. U šemi 2c, „X<a>“ je definisan kao O ili S. „LG“ je definisan kao odlazeća grupa kao što je, na primer, halogen, MsO ili TosO, poželjno TosO. Sve druge promenljive u šemi 2c su definisane u skladu sa opsegom predmetnog pronalaska. Stručnjaku će biti jasno da je odgovarajuća zaštitna grupa potrebna kada je R<3a>, R<3b>ili R<3c>-NH2ili -NHR<7b>. [0258] Intermediates III, V and VII, where Z represents -X<a>-CHR<5a>-, can be prepared according to scheme 2c. In Scheme 2c, "X<a>" is defined as O or S. "LG" is defined as a leaving group such as, for example, halogen, MsO or TosO, preferably TosO. All other variables in Scheme 2c are defined within the scope of the present invention. One skilled in the art will appreciate that an appropriate protecting group is required when R<3a>, R<3b> or R<3c> is -NH2 or -NHR<7b>.

[0259] U šemi 2c važe sledeći reakcioni uslovi: [0259] In Scheme 2c, the following reaction conditions apply:

1. 1: u prisustvu baze kao što je, na primer, K2CO3, Et3N ili DIPEA, u odgovarajućem rastvaraču kao što je CH3CN, DCM ili N,N-dimetilacetamid (DMA). 1. 1: in the presence of a base such as, for example, K2CO3, Et3N or DIPEA, in a suitable solvent such as CH3CN, DCM or N,N-dimethylacetamide (DMA).

[0260] Polazne supstance u šemi 2c su komercijalno dostupne, ili mogu da se pripreme na standardni način koji je očigledan stručnjacima, ili kao što je opisano u sledećim opštim šemama. Stručnjaku će biti jasno da, kada je R<5a>C1-4alkil, različiti izomeri mogu međusobno da se razdvoje koristeći reversno faznu tečnu hromatografiju visokih performansi (RP-HPLC) ili superkritičnu tečnu hromatografiju (SFC). [0260] The starting substances in Scheme 2c are commercially available, or can be prepared in a standard manner apparent to those skilled in the art, or as described in the following general schemes. One skilled in the art will appreciate that, when R<5a>C1-4alkyl, the different isomers can be separated from each other using reverse phase high performance liquid chromatography (RP-HPLC) or supercritical liquid chromatography (SFC).

Opšta šema 3 General scheme 3

[0261] Uopšteno, intermedijeri u kojima Z predstavlja -X-CHR<5a>-; i u kojima X predstavlja -NH- ili -NR<11>- mogu da se pripreme prema šemi 3. U šemi 3, „LG1“ je definisan kao odlazeća grupa kao što je, na primer, halogen; „LG2“ je definisan kao odlazeća grupa kao što je, na primer, halogen ili -SCH3. „LG3“ je definisan kao odlazeća grupa kao što je, na primer, halogen ili -SCH3. Sve druge promenljive u šemi 3 definisane su u skladu sa opsegom predmetnog pronalaska. [0261] In general, intermediates in which Z represents -X-CHR<5a>-; and wherein X represents -NH- or -NR<11>- can be prepared according to Scheme 3. In Scheme 3, "LG1" is defined as a leaving group such as, for example, halogen; "LG2" is defined as a leaving group such as, for example, halogen or -SCH3. "LG3" is defined as a leaving group such as, for example, halogen or -SCH3. All other variables in Scheme 3 are defined within the scope of the present invention.

[0262] U šemi 3 važe sledeći reakcioni uslovi: [0262] In Scheme 3, the following reaction conditions apply:

1. 1: u prisustvu odgovarajućeg redukcionog reagensa kao što je, na primer, natrijum triacetoksiborhidrid (NaBH(AcO)3) zajedno sa odgovarajućim rastvaračem kao što je, na primer, DCM, na odgovarajućoj temperaturi kao što je, na primer, sobna temperatura; ili, alternativno, NaBH3CN zajedno sa odgovarajućim rastvaračem kao što je, na primer, MeOH, na odgovarajućoj temperaturi kao što je, na primer, od sobne temperature do 50°C. 1. 1: in the presence of a suitable reducing reagent such as, for example, sodium triacetoxyborohydride (NaBH(AcO)3) together with a suitable solvent such as, for example, DCM, at a suitable temperature such as, for example, room temperature; or, alternatively, NaBH3CN together with a suitable solvent such as, for example, MeOH, at a suitable temperature such as, for example, from room temperature to 50°C.

2. 2: u prisustvu odgovarajuće baze kao što je, na primer, NaH, zajedno sa odgovarajućim rastvaračem kao što je, na primer, anhidrovani THF, N,N-dimetilformamid (DMF), DMA, na odgovarajućoj temperaturi kao što je, na primer, od sobne temperature do 50°C. 2. 2: in the presence of a suitable base such as, for example, NaH, together with a suitable solvent such as, for example, anhydrous THF, N,N-dimethylformamide (DMF), DMA, at a suitable temperature such as, for example, from room temperature to 50°C.

[0263] Polazne supstance u šemi 3 su komercijalno dostupne ili mogu da se pripreme na standardni način koji je očigledan stručnjacima, ili kao što je opisano u specifičnom eksperimentalnom delu. Stručnjaku će biti jasno da, kada je R<5a>C1-4alkil, različiti izomeri mogu međusobno da se razdvoje koristeći reversno faznu tečnu hromatografiju visokih performansi (RP-HPLC) ili superkritičnu tečnu hromatografiju (SFC). [0263] The starting substances in Scheme 3 are commercially available or can be prepared in a standard manner apparent to those skilled in the art, or as described in the specific experimental section. One skilled in the art will appreciate that, when R<5a>C1-4alkyl, the different isomers can be separated from each other using reverse phase high performance liquid chromatography (RP-HPLC) or supercritical liquid chromatography (SFC).

Opšta šema 4 General scheme 4

[0264] Uopšteno, intermedijeri u kojima Z predstavlja - C=C-, -CH=CH-, ili -CH2-CH2- mogu da se pripreme prema šemi 4. U šemi 4, „LG1“ je definisan kao odlazeća grupa kao što je, na primer, halogen; „LG2“ je definisan kao odlazeća grupa kao što je, na primer, halogen ili -SCH3. „LG3“ je definisan kao odlazeća grupa kao što je, na primer, halogen ili - SCH3. Sve druge promenljive u šemi 4 definisane su u skladu sa opsegom predmetnog pronalaska. [0264] In general, intermediates in which Z represents -C=C-, -CH=CH-, or -CH2-CH2- can be prepared according to Scheme 4. In Scheme 4, "LG1" is defined as a leaving group such as, for example, halogen; "LG2" is defined as a leaving group such as, for example, halogen or -SCH3. "LG3" is defined as a leaving group such as, for example, halogen or -SCH3. All other variables in Scheme 4 are defined within the scope of the present invention.

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[0265] U šemi 4 važe sledeći reakcioni uslovi: [0265] In Scheme 4, the following reaction conditions apply:

1. 1: U prisustvu odgovarajućeg amina, kao što je HNR'R" ili NaOR', sa odgovarajućim rastvaračem kao što je, na primer, H2O, MeOH, ili EtOH, na odgovarajućoj temperaturi kao što je, na primer, od 100-130°C, u mikrotalasnoj pećnici ili koristeći autoklav za zagrevanje. 1. 1: In the presence of a suitable amine, such as HNR'R" or NaOR', with a suitable solvent such as, for example, H2O, MeOH, or EtOH, at a suitable temperature such as, for example, 100-130°C, in a microwave oven or using an autoclave for heating.

2. 2: U prisustvu odgovarajućeg katalizatora, kao što je bis(trifenilfosfin)paladijum(II) dihlorid i bakar(I) jodid u odgovarajućem rastvaraču, kao što je 2-metiltetrahidrofuran, sa odgovarajućom bazom, kao što je, na primer, trietilamin na odgovarajućoj temperaturi, kao što je, na primer, 80°C. 2. 2: In the presence of a suitable catalyst, such as bis(triphenylphosphine)palladium(II) dichloride and copper(I) iodide in a suitable solvent, such as 2-methyltetrahydrofuran, with a suitable base, such as, for example, triethylamine at a suitable temperature, such as, for example, 80°C.

3. 3: u prisustvu odgovarajuće soli, kao što je, na primer, tetraetilamonijum hlorid (Et4NCl), u odgovarajućem rastvaraču, kao što je, na primer, DMF, sa odgovarajućom bazom, kao što je, na primer, DIPEA, i paladijumskim katalizatorom, kao što je, na primer, Pd(OAc)2(paladijum(II) acetat), na odgovarajućoj temperaturi, kao što je, na primer, 100°C. 3. 3: in the presence of a suitable salt, such as, for example, tetraethylammonium chloride (Et4NCl), in a suitable solvent, such as, for example, DMF, with a suitable base, such as, for example, DIPEA, and a palladium catalyst, such as, for example, Pd(OAc)2(palladium(II) acetate), at a suitable temperature, such as, for example, 100°C.

4. 4: u prisustvu atmosfere gasovitog H2i katalizatora, kao što je, na primer, Pd/C (na primer, 5 mas.% ili 10 mas.%) u odgovarajućem rastvaraču, kao što je, na primer, MeOH. 4. 4: in the presence of a gaseous H2i catalyst atmosphere, such as, for example, Pd/C (for example, 5 wt.% or 10 wt.%) in a suitable solvent, such as, for example, MeOH.

[0266] Polazne supstance u šemi 4 su komercijalno dostupne ili mogu da se pripreme na standardni način koji je očigledan stručnjacima, ili kao što je opisano u specifičnom eksperimentalnom delu. [0266] The starting substances in Scheme 4 are commercially available or can be prepared in a standard manner apparent to those skilled in the art, or as described in the specific experimental section.

Opšta šema 5 General scheme 5

[0267] Uopšteno, intermedijeri u kojima Y predstavlja CH2ili CF2, ovde nazvan Y<a>, i u kojima Z predstavlja -CH2O- mogu da se pripreme prema šemi 5. [0267] In general, intermediates in which Y is CH 2 or CF 2 , herein referred to as Y<a>, and in which Z is -CH 2 O- can be prepared according to Scheme 5.

[0268] U šemi 5, „LG1“ je definisan kao odlazeća grupa kao što je, na primer, halogen; „LG2“ je definisan kao odlazeća grupa kao što je, na primer, halogen ili -SCH3. „LG3“ je definisan kao odlazeća grupa kao što je halogen ili -SCH3. Sve druge promenljive u šemi 5 definisane su u skladu sa opsegom predmetnog pronalaska. [0268] In Scheme 5, "LG1" is defined as a leaving group such as, for example, halogen; "LG2" is defined as a leaving group such as, for example, halogen or -SCH3. "LG3" is defined as a leaving group such as halogen or -SCH3. All other variables in Scheme 5 are defined within the scope of the present invention.

[0269] U šemi 5 važe sledeći reakcioni uslovi: [0269] In Scheme 5, the following reaction conditions apply:

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1. 1: u prisustvu baze kao što je, na primer, K2CO3, Et3N ili DIPEA, u odgovarajućem rastvaraču kao što je CH3CN, DCM ili N,N-dimetilacetamid (DMA). 1. 1: in the presence of a base such as, for example, K2CO3, Et3N or DIPEA, in a suitable solvent such as CH3CN, DCM or N,N-dimethylacetamide (DMA).

Opšta šema 6 General scheme 6

[0270] Uopšteno, intermedijeri u kojima Z predstavlja -CH2- mogu da se pripreme prema šemi 6. U šemi 6, „LG1“ je definisan kao odlazeća grupa kao što je, na primer, halogen; „LG2“ je definisan kao odlazeća grupa kao što je, na primer, halogen ili -SCH3. „LG3“ je definisan kao odlazeća grupa kao što je, na primer, halogen ili -SCH3. Sve druge promenljive u šemi 6 definisane su u skladu sa opsegom predmetnog pronalaska. [0270] In general, intermediates in which Z is -CH2- can be prepared according to Scheme 6. In Scheme 6, "LG1" is defined as a leaving group such as, for example, halogen; "LG2" is defined as a leaving group such as, for example, halogen or -SCH3. "LG3" is defined as a leaving group such as, for example, halogen or -SCH3. All other variables in Scheme 6 are defined within the scope of the present invention.

[0271] U šemi 6 važe sledeći reakcioni uslovi: [0271] In Scheme 6, the following reaction conditions apply:

1. 1: U prisustvu tozilhidrazida, sa odgovarajućim rastvaračem, kao što je, na primer, MeOH, EtOH ili DCM, na odgovarajućoj temperaturi, kao što je sobna temperatura. 1. 1: In the presence of tosylhydrazide, with a suitable solvent, such as, for example, MeOH, EtOH or DCM, at a suitable temperature, such as room temperature.

2. 2: U prisustvu boronske kiseline, sa odgovarajućom bazom kao što je K2CO3, Na2CO3, Cs2CO3, sa odgovarajućim rastvaračem kao što je, na primer, 1,4-dioksan, na odgovarajućoj temperaturi kao što je 90°C. 2. 2: In the presence of boronic acid, with a suitable base such as K2CO3, Na2CO3, Cs2CO3, with a suitable solvent such as, for example, 1,4-dioxane, at a suitable temperature such as 90°C.

14 14

[0272] Polazne supstance u šemi 6 su komercijalno dostupne ili mogu da se pripreme na standardni način koji je očigledan stručnjacima, ili kao što je opisano u specifičnom eksperimentalnom delu. [0272] The starting substances in Scheme 6 are commercially available or can be prepared in a standard manner apparent to those skilled in the art, or as described in the specific experimental section.

Opšta šema 7 General scheme 7

[0273] Uopšteno, intermedijeri u kojima Z predstavlja -CH2-CH2- mogu da se pripreme prema šemi 7. U šemi 7, „LG1“ je definisan kao odlazeća grupa kao što je, na primer, halogen; „LG2“ je definisan kao odlazeća grupa kao što je, na primer, halogen ili -SCH3. „LG3“ je definisan kao odlazeća grupa kao što je, na primer, halogen ili -SCH3. Sve druge promenljive u šemi 7 definisane su u skladu sa opsegom predmetnog pronalaska. [0273] In general, intermediates in which Z represents -CH2-CH2- can be prepared according to Scheme 7. In Scheme 7, "LG1" is defined as a leaving group such as, for example, halogen; "LG2" is defined as a leaving group such as, for example, halogen or -SCH3. "LG3" is defined as a leaving group such as, for example, halogen or -SCH3. All other variables in Scheme 7 are defined within the scope of the present invention.

[0274] U šemi 7 obično važe sledeći reakcioni uslovi: [0274] In Scheme 7, the following reaction conditions usually apply:

1: U prvom koraku u prisustvu alkenskog prekursora i 0,5 M rastvora 9-borabiciklo(3.3.1)nonana (9-BBN) u THF-u u atmosferi azota, na temperaturi od sobne temperature do refluksa, i sa trajanjem reakcije od 1 do 3 sata. U drugom koraku u prisustvu, na primer, odgovarajućeg Ar-bromida ili Ar-jodida i odgovarajućeg katalizatora, kao što je, na primer, 1,1'-bis(difenilfosfino)ferocen]dihlorpaladijum(II) i u prisustvu odgovarajuće baze, kao što je, na primer, trikalijum fosfat, u odgovarajućoj 1: In the first step in the presence of an alkene precursor and a 0.5 M solution of 9-borabicyclo(3.3.1)nonane (9-BBN) in THF under a nitrogen atmosphere, at a temperature from room temperature to reflux, and with a reaction time of 1 to 3 hours. In a second step in the presence of, for example, a suitable Ar-bromide or Ar-iodide and a suitable catalyst, such as, for example, 1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) and in the presence of a suitable base, such as, for example, tripotassium phosphate, in a suitable

14 14

smeši rastvarača, kao što su, na primer THF i voda, na odgovarajućoj temperaturi od 50°C do refluksa, i sa odgovarajućim trajanjem reakcije od 1 do 3 sata. solvent mixture, such as, for example, THF and water, at a suitable temperature of 50°C to reflux, and with a suitable reaction time of 1 to 3 hours.

2: Različiti skupovi reakcionih uslova u zavisnosti od definicije R<3a>, R<3b>ili R<3c>: 2: Different sets of reaction conditions depending on the definition of R<3a>, R<3b> or R<3c>:

2a: Kada je R<3a>, R<3b>ili R<3c>halogen, korak 1 može da se preskoči. 2a: When R<3a>, R<3b>or R<3c>is halogen, step 1 can be skipped.

2b: Kada je R<3a>, R<3b>ili R<3c>NR<7a>R<7b>, u prisustvu odgovarajućeg amina formule HNR<7a>R<7b>, sa odgovarajućim rastvaračem kao što je, na primer, H2O, MeOH, ili EtOH, na odgovarajućoj temperaturi kao što je, na primer, 100-130°C, obično u uslovima mikrotalasne pećnice ili koristeći autoklav za zagrevanje. 2b: When R<3a>, R<3b>or R<3c>NR<7a>R<7b>, in the presence of a suitable amine of the formula HNR<7a>R<7b>, with a suitable solvent such as, for example, H2O, MeOH, or EtOH, at a suitable temperature such as, for example, 100-130°C, usually under microwave conditions or using an autoclave for heating.

2c: Kada je R<3a>, R<3b>ili R<3c>-O-C1-4alkil, u prisustvu odgovarajućeg HO-C1-4alkila, sa odgovarajućom bazom kao što je, na primer, NaH, kalijum terc-butoksid (tBuOK) u odgovarajućem rastvaraču kao što je, na primer, tetrahidrofuran (THF) na odgovarajućoj temperaturi. Alternativno u prisustvu odgovarajućeg HO-C1-4alkila kao rastvarača sa odgovarajućom kiselinom, kao što je, na primer, HCl. 2c: When R<3a>, R<3b>or R<3c> is -O-C1-4alkyl, in the presence of a suitable HO-C1-4alkyl, with a suitable base such as, for example, NaH, potassium tert-butoxide (tBuOK) in a suitable solvent such as, for example, tetrahydrofuran (THF) at a suitable temperature. Alternatively in the presence of the appropriate HO-C 1-4 alkyl as solvent with a suitable acid such as, for example, HCl.

2d: Kada je R<3a>, R<3b>ili R<3c>vodonik, u uslovima hidrogenovanja: pod atmosferom gasovitog H2u prisustvu katalizatora kao što je, na primer, Reni Ni, Pd/C (na primer, 5 mas.% ili 10 mas.%) ili Pt/C (na primer, 5 mas.%) u odgovarajućem rastvaraču kao što je, na primer, metanol (MeOH), etanol (EtOH) ili THF; 2d: When R<3a>, R<3b>or R<3c> is hydrogen, under hydrogenation conditions: under an atmosphere of gaseous H2 in the presence of a catalyst such as, for example, Raney Ni, Pd/C (for example, 5 wt.% or 10 wt.%) or Pt/C (for example, 5 wt.%) in a suitable solvent such as, for example, methanol (MeOH), ethanol (EtOH) or THF;

2e: Kada je R<3a>, R<3b>ili R<3c>C1-4alkil, u prisustvu odgovarajuće boronske kiseline ili estra kao što je, na primer, metilboronska kiselina sa odgovarajućim katalizatorom kao što je, na primer, 1,1'-bis(difenilfosfino)ferocen, i sa odgovarajućom bazom kao što je, na primer, K3PO4, u odgovarajućoj smeši rastvarača kao što je, na primer, dioksan/H2O u odnosu 5 prema 1, na odgovarajućoj temperaturi, kao što je, na primer, 100°C. 2e: When R<3a>, R<3b>or R<3c> is C1-4alkyl, in the presence of a suitable boronic acid or ester such as, for example, methylboronic acid with a suitable catalyst such as, for example, 1,1'-bis(diphenylphosphino)ferrocene, and with a suitable base such as, for example, K3PO4, in a suitable solvent mixture such as, for example, dioxane/H2O in the ratio 5 to 1, at a suitable temperature, such as, for example, 100°C.

[0275] Polazne supstance u šemi 7 su komercijalno dostupne ili mogu da se pripreme na standardni način koji je očigledan stručnjacima, ili kao što je opisano u specifičnom eksperimentalnom delu. [0275] The starting substances in Scheme 7 are commercially available or can be prepared in a standard manner apparent to those skilled in the art, or as described in the specific experimental section.

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Opšta šema 8 General scheme 8

[0276] Uopšteno, intermedijeri u kojima Z predstavlja -CH2-CH2- mogu da se pripreme prema šemi 8. U šemi 8, „LG1“ je definisan kao odlazeća grupa kao što je, na primer, halogen; „LG2“ je definisan kao odlazeća grupa kao što je, na primer, halogen ili -SCH3. „LG3“ je definisan kao odlazeća grupa kao što je, na primer, halogen ili -SCH3. Sve druge promenljive u šemi 8 definisane su u skladu sa opsegom predmetnog pronalaska. [0276] In general, intermediates in which Z represents -CH2-CH2- can be prepared according to Scheme 8. In Scheme 8, "LG1" is defined as a leaving group such as, for example, halogen; "LG2" is defined as a leaving group such as, for example, halogen or -SCH3. "LG3" is defined as a leaving group such as, for example, halogen or -SCH3. All other variables in Scheme 8 are defined within the scope of the present invention.

[0277] U šemi 8 obično važe sledeći reakcioni uslovi: [0277] In Scheme 8, the following reaction conditions usually apply:

1: Različiti skupovi reakcionih uslova u zavisnosti od definicije R<3a>, R<3b>ili R<3c>: 1: Different sets of reaction conditions depending on the definition of R<3a>, R<3b> or R<3c>:

1a: Kada je R<3a>, R<3b>ili R<3c>halogen, korak 1 može da se preskoči. 1a: When R<3a>, R<3b>or R<3c>is halogen, step 1 can be skipped.

1b: Kada je R<3a>, R<3b>ili R<3c>NR<7a>R<7b>, u prisustvu odgovarajućeg amina formule HNR<7a>R<7b>, sa odgovarajućim rastvaračem kao što je, na primer, H2O, MeOH, ili EtOH, na odgovarajućoj temperaturi kao što je, na primer, 100-130°C, obično u uslovima mikrotalasne pećnice ili koristeći autoklav za zagrevanje. 1b: When R<3a>, R<3b>or R<3c>NR<7a>R<7b>, in the presence of a suitable amine of the formula HNR<7a>R<7b>, with a suitable solvent such as, for example, H2O, MeOH, or EtOH, at a suitable temperature such as, for example, 100-130°C, usually under microwave conditions or using an autoclave for heating.

1c: Kada je R<3a>, R<3b>ili R<3c>-O-C1-4alkil, u prisustvu odgovarajućeg HO-C1-4alkila, sa odgovarajućom bazom kao što je, na primer, NaH, kalijum terc-butoksid (tBuOK) u odgovarajućem rastvaraču kao što je, na primer, tetrahidrofuran (THF) na 1c: When R<3a>, R<3b>or R<3c> is -O-C1-4alkyl, in the presence of a suitable HO-C1-4alkyl, with a suitable base such as, for example, NaH, potassium tert-butoxide (tBuOK) in a suitable solvent such as, for example, tetrahydrofuran (THF) at

14 14

odgovarajućoj temperaturi. Alternativno u prisustvu odgovarajućeg HO-C1-4alkila kao rastvarača sa odgovarajućom kiselinom, kao što je, na primer, HCl. the appropriate temperature. Alternatively in the presence of the appropriate HO-C 1-4 alkyl as solvent with a suitable acid such as, for example, HCl.

1d: Kada je R<3a>, R<3b>ili R<3c>vodonik, u uslovima hidrogenovanja: pod atmosferom gasovitog H2u prisustvu katalizatora kao što je, na primer, Reni Ni, Pd/C (na primer, 5 mas.% ili 10 mas.%) ili Pt/C (na primer, 5 mas.%) u odgovarajućem rastvaraču kao što je, na primer, metanol (MeOH), etanol (EtOH) ili THF; 1d: When R<3a>, R<3b>or R<3c> is hydrogen, under hydrogenation conditions: under an atmosphere of gaseous H2 in the presence of a catalyst such as, for example, Raney Ni, Pd/C (for example, 5 wt.% or 10 wt.%) or Pt/C (for example, 5 wt.%) in a suitable solvent such as, for example, methanol (MeOH), ethanol (EtOH) or THF;

1e: Kada je R<3a>, R<3b>ili R<3c>C1-4alkil, u prisustvu odgovarajuće boronske kiseline ili estra kao što je, na primer, metil boronska kiselina sa odgovarajućim katalizatorom kao što je, na primer, 1,1'-bis(difenilfosfino)ferocen i sa odgovarajućom bazom kao što je, na primer, K3PO4u odgovarajućoj smeši rastvarača kao što je, na primer, dioksan/H2O u odnosu 5 prema 1 na odgovarajućoj temperaturi, kao što je, na primer, 100°C; 1e: When R<3a>, R<3b>or R<3c> is C1-4alkyl, in the presence of a suitable boronic acid or ester such as, for example, methyl boronic acid with a suitable catalyst such as, for example, 1,1'-bis(diphenylphosphino)ferrocene and with a suitable base such as, for example, K3PO4 in a suitable solvent mixture such as, for example, dioxane/H2O in a ratio of 5 1 at a suitable temperature, such as, for example, 100°C;

2: U prvom koraku u prisustvu alkenskog prekursora i 0,5 M rastvora 9-BBN u THF-u u atmosferi azota, na temperaturi od sobne temperature do refluksa, i sa trajanjem reakcije od 1 do 3 sata. U drugom koraku u prisustvu odgovarajućeg (het)aril bromida ili (het)aril jodida i odgovarajućeg katalizatora, kao što je, na primer, 1,1'-bis(difenilfosfino)ferocen]dihlorpaladijum(II) i u prisustvu odgovarajuće baze, kao što je, na primer, trikalijum fosfat, u odgovarajućoj smeši rastvarača, kao što su, na primer, THF i voda, na odgovarajućoj temperaturi od 50°C do refluksa, i sa odgovarajućim trajanjem reakcije od 1 do 3 sata. 2: In the first step in the presence of an alkene precursor and a 0.5 M solution of 9-BBN in THF under a nitrogen atmosphere, at a temperature from room temperature to reflux, and with a reaction time of 1 to 3 hours. In a second step in the presence of a suitable (het)aryl bromide or (het)aryl iodide and a suitable catalyst, such as, for example, 1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) and in the presence of a suitable base, such as, for example, tripotassium phosphate, in a suitable solvent mixture, such as, for example, THF and water, at a suitable temperature of 50°C to reflux, and with a suitable duration reactions from 1 to 3 hours.

[0278] Polazne supstance u šemi 8 su komercijalno dostupne ili mogu da se pripreme na standardni način koji je očigledan stručnjacima, ili kao što je opisano u specifičnom eksperimentalnom delu. [0278] The starting substances in Scheme 8 are commercially available or can be prepared in a standard manner apparent to those skilled in the art, or as described in the specific experimental section.

Opšta šema 9 General scheme 9

[0279] Uopšteno, intermedijeri prikazani u šemi 9 u kojima Z predstavlja -CH2-CH2- mogu da se pripreme prema šemi 9. U šemi 9, „LG1“ je definisan kao odlazeća grupa kao što je, na primer, halogen. Sve druge promenljive u šemi 9 su definisane u skladu sa opsegom predmetnog pronalaska [0279] In general, the intermediates shown in Scheme 9 wherein Z represents -CH2-CH2- can be prepared according to Scheme 9. In Scheme 9, "LG1" is defined as a leaving group such as, for example, halogen. All other variables in Scheme 9 are defined within the scope of the present invention

1 1

1. 1: U prvom koraku u prisustvu alkenskog prekursora i 0,5 M rastvora 9-BBN u THF-u u atmosferi azota, na temperaturi od sobne temperature do refluksa, i sa trajanjem reakcije od 1 do 3 sata. U drugom koraku u prisustvu, na primer, odgovarajućeg Arbromida ili Ar-jodida (gde je X Br, odnosno I) i odgovarajućeg katalizatora, kao što je, na primer 1,1'-bis(difenilfosfino)ferocen]dihlorpaladijum(II), i u prisustvu odgovarajuće baze, kao što je na primer, trikalijum fosfat, u odgovarajućoj smeši rastvarača, kao što su, na primer, THF i voda, na odgovarajućoj temperaturi od 50°C do refluksa, i sa odgovarajućim trajanjem reakcije od 1 do 3 sata. 1. 1: In the first step in the presence of an alkene precursor and a 0.5 M solution of 9-BBN in THF under a nitrogen atmosphere, at a temperature from room temperature to reflux, and with a reaction time of 1 to 3 hours. In a second step in the presence of, for example, a suitable Arbromide or Ar-iodide (where X is Br, i.e. I) and a suitable catalyst, such as, for example, 1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), and in the presence of a suitable base, such as, for example, tripotassium phosphate, in a suitable solvent mixture, such as, for example, THF and water, at a suitable temperature of 50°C to reflux, and with with a corresponding reaction time of 1 to 3 hours.

2. 2: U prisustvu anhidrida trifluormetansulfonske kiseline i odgovarajuće baze, kao što je, na primer, piridin, u odgovarajućem rastvaraču, kao što je, na primer, DCM, na odgovarajućoj temperaturi, kao što je, na primer, 0°C, u inertnoj atmosferi gasovitog N2. 2. 2: In the presence of trifluoromethanesulfonic acid anhydride and a suitable base, such as, for example, pyridine, in a suitable solvent, such as, for example, DCM, at a suitable temperature, such as, for example, 0°C, under an inert atmosphere of N2 gas.

3. 3: U prisustvu odgovarajuće baze, kao što je, na primer, Cs2CO3, u odgovarajućem rastvaraču, kao što je, na primer, DMF, na odgovarajućoj temperaturi, kao što je, na primer, sobna temperatura, u inertnoj atmosferi gasovitog N2. 3. 3: In the presence of a suitable base, such as, for example, Cs2CO3, in a suitable solvent, such as, for example, DMF, at a suitable temperature, such as, for example, room temperature, under an inert atmosphere of N2 gas.

[0280] Polazne supstance u šemi 9 su komercijalno dostupne ili mogu da se pripreme na standardni način koji je očigledan stručnjacima, ili kao što je opisano u specifičnom eksperimentalnom delu. [0280] The starting substances in Scheme 9 are commercially available or can be prepared in a standard manner apparent to those skilled in the art, or as described in the specific experimental section.

[0281] U svim ovim pripremama, reakcioni proizvodi mogu da se izoluju iz reakcionog medijuma i, ako je to potrebno, dalje da se prečiste u skladu sa metodologijom koja je uopšteno poznata u struci, poput, na primer, ekstrakcije, kristalizacije, trituracije i hromatografije. [0281] In all these preparations, the reaction products can be isolated from the reaction medium and, if necessary, further purified according to methodology generally known in the art, such as, for example, extraction, crystallization, trituration and chromatography.

1 1 1 1

[0282] Hiralno čisti oblici jedinjenja formule (I) čine poželjnu grupu jedinjenja. Stoga su hiralno čisti oblici intermedijera i njihovi oblici soli naročito korisni u pripremi hiralno čistih jedinjenja formule (I). Enantiomerne smeše intermedijera su takođe korisne u pripremi jedinjenja formule (I) odgovarajuće konfiguracije. [0282] Chirally pure forms of compounds of formula (I) form a preferred group of compounds. Therefore, chirally pure forms of intermediates and their salt forms are particularly useful in the preparation of chirally pure compounds of formula (I). Enantiomeric mixtures of intermediates are also useful in the preparation of compounds of formula (I) of appropriate configuration.

Farmakologija Pharmacology

[0283] Otkriveno je da jedinjenja iz predmetnog pronalaska inhibiraju aktivnost PRMT5. [0283] Compounds of the present invention have been found to inhibit PRMT5 activity.

[0284] Konkretno, jedinjenja iz predmetnog pronalaska se vezuju za enzim PRMT5, i kompetitivno sa prirodnim supstratom SAM (S-adenozil-L-metionin), inhibirajući taj enzim. [0284] In particular, the compounds of the present invention bind to the enzyme PRMT5, and competitively with the natural substrate SAM (S-adenosyl-L-methionine), inhibiting that enzyme.

[0285] Stoga se predviđa da jedinjenja prema predmetnom pronalasku ili njihove farmaceutske kompozicije mogu biti korisni za lečenje ili prevenciju, naročito lečenje, bolesti kao što su hematološki poremećaj, metabolički poremećaji, autoimunski poremećaji, kancer, inflamatorne bolesti, kardiovaskularne bolesti, neurodegenerativne bolesti, pankreatitis, zatajenje više organa, bolesti bubrega, agregacija trombocita, pokretljivost sperme, odbacivanje transplantata, odbacivanje grafta, povrede pluća, i slično. [0285] Therefore, it is envisaged that the compounds according to the present invention or their pharmaceutical compositions may be useful for the treatment or prevention, especially the treatment, of diseases such as hematological disorders, metabolic disorders, autoimmune disorders, cancer, inflammatory diseases, cardiovascular diseases, neurodegenerative diseases, pancreatitis, multiple organ failure, kidney diseases, platelet aggregation, sperm motility, transplant rejection, graft rejection, lung injuries, and the like.

[0286] Konkretno, jedinjenja prema predmetnom pronalasku ili njihove farmaceutske kompozicije mogu biti korisni za lečenje ili prevenciju, naročito lečenje, bolesti kao što su alergija, astma, kancer hematopoetskog sistema, kancer pluća, kancer prostate, melanom, metabolički poremećaj, dijabetes, gojaznost, hematološki poremećaj, anemija srpastih ćelija, i slično. [0286] In particular, the compounds according to the present invention or their pharmaceutical compositions can be useful for the treatment or prevention, especially the treatment, of diseases such as allergy, asthma, cancer of the hematopoietic system, lung cancer, prostate cancer, melanoma, metabolic disorder, diabetes, obesity, hematological disorder, sickle cell anemia, and the like.

[0287] Jedinjenja prema predmetnom pronalasku ili njihove farmaceutske kompozicije mogu biti korisni za lečenje ili prevenciju, naročito lečenje, bolesti kao što je proliferativni poremećaj, kao što je autoimunska bolest, kancer, benigna neoplazma, ili inflamatorna bolest. [0287] The compounds of the present invention or their pharmaceutical compositions may be useful for the treatment or prevention, in particular the treatment, of a disease such as a proliferative disorder, such as an autoimmune disease, cancer, a benign neoplasm, or an inflammatory disease.

[0288] Jedinjenja prema predmetnom pronalasku ili njihove farmaceutske kompozicije mogu biti korisni za lečenje ili prevenciju, naročito lečenje, bolesti kao što je metabolički poremećaj koji obuhvata dijabetes, gojaznost; proliferativni poremećaj koji obuhvata kancer, kancer hematopoetskog sistema, kancer pluća, kancer prostate, melanom ili kancer pankreasa; [0288] The compounds of the present invention or their pharmaceutical compositions may be useful for the treatment or prevention, in particular the treatment, of diseases such as metabolic disorders including diabetes, obesity; a proliferative disorder including cancer, cancer of the hematopoietic system, lung cancer, prostate cancer, melanoma or pancreatic cancer;

1 2 1 2

hematološki poremećaj; hemoglobinopatija; anemija srpastih ćelija; β- talasemija, inflamatorna bolest i autoimunska bolest, npr. reumatoidni artritis, sistemski eritemski lupus, Šegrenov sindrom, dijareja, gastroezofagealna refluksna bolest, i slično. hematological disorder; hemoglobinopathy; sickle cell anemia; β-thalassemia, inflammatory disease and autoimmune disease, e.g. rheumatoid arthritis, systemic lupus erythematosus, Sjogren's syndrome, diarrhea, gastroesophageal reflux disease, and the like.

[0289] U nekim otelotvorenjima, inhibicija PRMT5 putem obezbeđenog jedinjenja može biti korisna u lečenju ili prevenciji, naročito lečenju, sledećeg neograničavajućeg spiska kancera: kancera dojke, kancera pluća, kancera jednjaka, kancera mokraćne bešike, kancera hematopoetskog sistema, limfoma, meduloblastoma, adenokarcinoma rektuma, adenokarcinoma debelog creva, kancera želuca, kancera pankreasa, kancera jetre, adenoidnog cističnog karcinoma, adenokarcinoma pluća, karcinoma skvamoznih ćelija glave i vrata, moždanih tumora, hepatocelularnog karcinoma, karcinoma bubrežnih ćelija, melanoma, oligodendroglioma, karcinoma ćelija jajnika i seroznog cistadenoma jajnika. [0289] In some embodiments, inhibition of PRMT5 by a provided compound may be useful in the treatment or prevention, particularly the treatment, of the following non-limiting list of cancers: breast cancer, lung cancer, esophageal cancer, bladder cancer, hematopoietic system cancer, lymphoma, medulloblastoma, rectal adenocarcinoma, colon adenocarcinoma, gastric cancer, pancreatic cancer, liver cancer, adenoid cystic carcinoma, adenocarcinoma of the lung, squamous cell carcinoma of the head and neck, brain tumors, hepatocellular carcinoma, renal cell carcinoma, melanoma, oligodendroglioma, ovarian cell carcinoma, and ovarian serous cystadenoma.

[0290] Primeri za metaboličke poremećaje koji mogu da se leče ili spreče, naročito leče, uključuju, ali nisu ograničeni na, dijabetes ili gojaznost. [0290] Examples of treatable or preventable metabolic disorders, particularly treatable, include, but are not limited to, diabetes or obesity.

[0291] Primeri za hematološke poremećaje koji mogu da se leče ili spreče, naročito leče, uključuju, ali nisu ograničeni na, hemoglobinopatiju, kao što je bolest srpastih ćelija ili βtalasemija. [0291] Examples of treatable or preventable hematological disorders, particularly treatable, include, but are not limited to, hemoglobinopathy, such as sickle cell disease or βthalassemia.

[0292] Primeri za kancere koji mogu da se leče ili spreče, naročito leče, uključuju, ali nisu ograničeni na, akustični neurom, adenokarcinom, kancer nadbubrežne žlezde, kancer anusa, angiosarkom (npr. limfangiosarkom, limfangioendotelijalni sarkom, hemangiosarkom), kancer slepog creva, benignu monoklonsku gamopatiju, kancer žučnog trakta (npr. holangiokarcinom), kancer mokraćne bešike, kancer dojke (npr. adenokarcinom dojke, papilarni karcinom dojke, kancer mlečne žlezde, medularni karcinom dojke), kancer mozga (npr. meningiom; gliom, npr. astrocitom, oligodendrogliom; meduloblastom), bronhijalni kancer, karcinoidni tumor, kancer grlića materice (npr. adenokarcinom grlića materice), hordom, horiokarcinom, kraniofaringiom, kolorektalni kancer (npr. kancer debelog creva, kancer rektuma, kolorektalni adenokarcinom), epitelni karcinom, ependimom, endoteliosarkom (npr. Kapošijev sarkom, multiplli idiopatski hemoragijski sarkom), kancer endometriuma (npr. kancer materice, sarkom materice), kancer jednjaka (npr adenokarcinom jednjaka, Baretov adenokarcinom), Juingov sarkom, kancer oka (npr. intraokularni melanom, retinoblastom), familijarnu hipereozinofiliju, kancer žučne kese, kancer želuca (npr. adenokarcinom želuca), gastrointestinalni stromalni tumor (GIST), kancer [0292] Examples of cancers that can be treated or prevented, particularly treatable, include, but are not limited to, acoustic neuroma, adenocarcinoma, adrenal cancer, anal cancer, angiosarcoma (eg, lymphangiosarcoma, lymphangioendothelial sarcoma, hemangiosarcoma), appendix cancer, benign monoclonal gammopathy, biliary tract cancer (eg, cholangiocarcinoma), urinary bladder, breast cancer (eg, breast adenocarcinoma, papillary breast cancer, mammary gland cancer, medullary breast cancer), brain cancer (eg, meningioma; glioma, eg, astrocytoma, oligodendroglioma; medulloblastoma), bronchial cancer, carcinoid tumor, cervical cancer (eg, cervical adenocarcinoma), chordoma, choriocarcinoma, craniopharyngioma, colorectal cancer (eg, cancer colon, rectal, colorectal cancer adenocarcinoma), epithelial carcinoma, ependymoma, endotheliosarcoma (eg, Kaposi's sarcoma, multiple idiopathic hemorrhagic sarcoma), endometrial cancer (eg, uterine cancer, uterine sarcoma), esophageal cancer (eg, esophageal adenocarcinoma, Barrett's adenocarcinoma), Ewing's sarcoma, eye cancer (eg, intraocular melanoma, retinoblastoma), familial hypereosinophilia, gallbladder cancer, gastric cancer (eg gastric adenocarcinoma), gastrointestinal stromal tumor (GIST), cancer

1 1

glave i vrata (npr. karcinom skvamoznih ćelija glave i vrata, oralni kancer (npr. karcinom oralnih skvamoznih ćelija (OSCC), kancer grla (npr. fkarcinom ždrela, kancer larinksa, kancer nazofarinksa, kancer orofarinksa)), kancere hematopoetskog sistema (npr. leukemija, kao što je akutna limfocitna leukemija (ALL) (npr. ALL B-ćelija, ALL T-ćelija), akutna mijelocitna leukemija (AML) (npr. AML B-ćelija, AML T-ćelija), hronična mijelocitna leukemija (CML) (npr. CML B-ćelija, CML T-ćelija) i hronična limfocitna leukemija (CLL) (npr. CLL B-ćelija, CLL T-ćelija); limfom, kao što je Hodžkinov limfom (HL) (npr. HL B-ćelija, HL T-ćelija) i non-Hodžkinov limfom (NHL) (npr. NHL B-ćelija, kao što je difuzni limfom velikih ćelija (DLCL) (npr. difuzni limfom velikih B-ćelija (DLBCL)), folikularni limfom, hroničnu lumfocitnu leukemiju/mali limfocitni limfom (CLL/SLL), limfom ćelija omotača (MCL), limfome B-ćelija marginalne zone (npr. limfomi limfoidnog tkiva povezanog sa sluznicom (MALT), nodalni limfom B-ćelija marginalne zone, limfom B-ćelija marginalne zone slezine), primarni medijastinalni B-ćelijski limfom, Burkitov limfom, limfoplazmacitni limfom (tj. „Valdenstromova makroglobulinemija“), imunoblastni limfom velikih ćelija, leukemiju vlasastih ćelija (HCL), prekursorski B-limfoblastni limfom i primarni limfom centralnog nervnog sistema (CNS); i T-ćelijski NHL, kao što je prekursorski T-limfoblastni limfom/leukemija, periferni limfom T-ćelija (PTCL) (npr. kutani limfom T-ćelija (CTCL) (npr. mycosis fungiodes, Sezarijev sindrom), angioimunoblastni limfom T-ćelija, ekstranodalni limfom T-ćelija prirodnih ubica, limfom T-ćelija enteropatskog tipa, limfom T-ćelija nalik supkutanom panikulitisu, anaplastični limfom velikih ćelija); mešavinu jedne ili više prethodno opisanih leukemija/limfoma; i multipli mijelom (MM)), bolest teškog lanca (npr. bolest alfa lanca, bolest gama lanca, bolest mi lanca), hemangioblastom, inflamatorne miofibroblastne tumore, imunocitnu amiloidozu, kancer bubrega (npr. nefroblastom tj. Vilmsov tumor, karcinom bubrežnih ćelija), kancer jetre (npr. hepatocelularni kancer (HCC), maligni hepatom), kancer pluća (npr. bronhogeni karcinom, nemikrocelularni kancer (NSCLC), skvamozni kancer pluća (SLC), adenokarcinom pluća, Luisov karcinom pluća, neuroendokrini tumori pluća: tipični karcinoid, atipični karcinoid, mikrocelularni kancer pluća (SCLC) i neuroendokrini karcinom velikih ćelija), lejomiosarkom (LMS), mastocitozu (npr. sistemska mastocitoza), mijelodisplastične sindrome (MDS), mezoteliom, mijeloproliferativni poremećaj (MPD) (npr. policitemija vera (PV), esencijalna trombocitoza (ET), agnogena mijeloidna metaplazija (AMM) tj. mijelofibroza (MF), hronična idiopatska mijelofibroza, hronična mijelocitna leukemija (CML), hronična neutrofilna leukemija (CNL), hipereozinofilni sindrom (HES)), neuroblastom, neurofibrom (npr. neurofibromatoza (NF) tip 1 ili tip 2, švanomatoza), neuroendokrini kancer (npr. gastroenteropankreasni neuroendokrini tumor (GEP-NET), head and neck (eg, head and neck squamous cell carcinoma, oral cancer (eg, oral squamous cell carcinoma (OSCC), throat cancer (eg, pharyngeal carcinoma, laryngeal cancer, nasopharyngeal cancer, oropharyngeal cancer)), cancers of the hematopoietic system (eg, leukemia, such as acute lymphocytic leukemia (ALL) (eg, B-cell ALL, T-cell ALL), acute myelocytic leukemia (AML) (eg AML B-cell, AML T-cell), chronic myelocytic leukemia (CML) (eg CML B-cell, CML T-cell) and chronic lymphocytic leukemia (CLL) (eg CLL B-cell, CLL T-cell); lymphoma, such as Hodgkin lymphoma (HL) (eg HL B-cell, HL T-cell) and non-Hodgkin lymphoma (NHL) (eg NHL B-cell, such as diffuse large cell lymphoma (DLCL) (eg diffuse large B-cell lymphoma (DLBCL)), follicular lymphoma, chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), mantle cell lymphoma (MCL), marginal zone B-cell lymphomas (eg mucosa-associated lymphoid tissue (MALT) lymphomas, nodal marginal zone B-cell lymphoma, marginal zone B-cell lymphoma spleen), primary mediastinal B-cell lymphoma, Burkitt's lymphoma, lymphoplasmacytic lymphoma (ie, "Waldenstrom's macroglobulinemia"), large cell immunoblastic lymphoma, hairy cell leukemia (HCL), precursor B-lymphoblastic lymphoma, and primary central nervous system (CNS) lymphoma; and T-cell NHL, such as precursor T-lymphoblastic lymphoma/leukemia, peripheral T-cell lymphoma (PTCL) (eg, cutaneous T-cell lymphoma (CTCL) (eg, mycosis fungiodes, Sézary syndrome), angioimmunoblastic T-cell lymphoma, extranodal natural killer T-cell lymphoma, enteropathic-type T-cell lymphoma, subcutaneous panniculitis-like T-cell lymphoma, anaplastic large cell lymphoma); a mixture of one or more of the previously described leukemias/lymphomas; and multiple myeloma (MM)), heavy chain disease (eg alpha chain disease, gamma chain disease, mi chain disease), hemangioblastoma, inflammatory myofibroblastic tumors, immunocytic amyloidosis, kidney cancer (eg nephroblastoma ie Wilms tumor, renal cell carcinoma), liver cancer (eg hepatocellular carcinoma (HCC), malignant hepatoma), lung cancer (eg bronchogenic carcinoma, non-small cell carcinoma (NSCLC), squamous lung cancer (SLC), adenocarcinoma of the lung, Lewis lung carcinoma, neuroendocrine tumors of the lung: typical carcinoid, atypical carcinoid, small cell lung cancer (SCLC) and large cell neuroendocrine carcinoma), leiomyosarcoma (LMS), mastocytosis (eg systemic mastocytosis), myelodysplastic syndromes (MDS), mesothelioma, myeloproliferative disorder (MPD) (eg polycythemia vera (PV), essential thrombocytosis (ET), agnogenic myeloid metaplasia (AMM) i.e. myelofibrosis (MF), chronic idiopathic myelofibrosis, chronic myelocytic leukemia (CML), chronic neutrophilic leukemia (CNL), hypereosinophilic syndrome (HES)), neuroblastoma, neurofibroma (eg neurofibromatosis (NF) type 1 or type 2, schwannomatosis), neuroendocrine cancer (eg gastroenteropancreatic neuroendocrine tumor (GEP-NET),

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karcinoidni tumor), osteosarkom, kancer jajnika (npr. cistadenokarcinom, embrionski kancer jajnika, adenokarcinom jajnika), papilarni adenokarcinom, kancer pankreasa (npr. andenokarcinom pankreasa, intraduktalna papilarna mucinozna neoplazma (IPMN), tumor ćelija ostrvaca), tumori ćelijskih ostrvaca), kancer penisa (npr. Padžetova bolest penisa i skrotuma), pinealom, primitivni neuroektodermalni tumor (PNT), kancer prostate (npr. adenokarcinom prostate), kancer rektuma, rabdomiosarkom, kancer pljuvačne žlezde, kancer kože (npr. karcinom skvamoznih ćelija (SCC), keratoakantom (KA), melanom, karcinom bazalnih ćelija (BCC)), kancer tankog creva (npr. kancer slepog creva), sarkom mekog tkiva (npr. maligni fibrozni histiocitom (MFH), liposarkom, maligni tumor perifernog nervnog omotača (MPNST), hondrosarkom, fibrosarkom, miksosarkom), karcinom lojne žlezde, karcinom znojne žlezde, sinoviom, kancer testisa (npr. seminom, embrionalni karcinom testisa), kancer tiroidne žlezde (npr. papilarni karcinom tiroidne žlezde, papilarni tiroidni karcinom (PTC), medularni tiroidni kancer), kancer uretre, vaginalni kancer i kancer vulve (npr. Padžetova bolest vulve). carcinoid tumor), osteosarcoma, ovarian cancer (eg, cystadenocarcinoma, embryonal ovarian cancer, ovarian adenocarcinoma), papillary adenocarcinoma, pancreatic cancer (eg, pancreatic adenocarcinoma, intraductal papillary mucinous neoplasm (IPMN), islet cell tumor), islet cell tumors), penile cancer (eg, Paget's disease of the penis and scrotum), pinealoma, primitive neuroectodermal tumor (PNT), prostate cancer (e.g. prostate adenocarcinoma), rectal cancer, rhabdomyosarcoma, salivary gland cancer, skin cancer (e.g. squamous cell carcinoma (SCC), keratoacanthoma (KA), melanoma, basal cell carcinoma (BCC)), small bowel cancer (e.g. appendix cancer), soft tissue sarcoma (e.g. malignant fibrous histiocytoma (MFH), liposarcoma, malignant tumor of peripheral nerve sheath (MPNST), chondrosarcoma, fibrosarcoma, myxosarcoma), sebaceous gland carcinoma, sweat gland carcinoma, synovioma, testicular cancer (e.g. seminoma, embryonal testicular carcinoma), thyroid cancer (e.g. papillary thyroid carcinoma, papillary thyroid carcinoma (PTC), medullary thyroid cancer), urethral cancer, vaginal cancer and vulvar cancer (e.g. Paget's disease of the vulva).

[0293] Primeri za neurodegenerativne bolesti koje mogu da se leče ili spreče, naročito leče, uključuju, bez ograničenja, bolest motornih neurona, progresivnu supranuklearnu paralizu, kortikobazalnu degeneraciju, Pikovu bolest, Alchajmerovu bolest, demenciju povezanu sa AIDS-om, Parkinsonovu bolest, amiotrofnu lateralnu sklerozu, retinitis pigmentozu, spinalnu mišićnu atrofiju i cerebelarnu degeneraciju. [0293] Examples of neurodegenerative diseases that can be treated or prevented, especially treated, include, without limitation, motor neuron disease, progressive supranuclear palsy, corticobasal degeneration, Pick's disease, Alzheimer's disease, AIDS-related dementia, Parkinson's disease, amyotrophic lateral sclerosis, retinitis pigmentosa, spinal muscular atrophy, and cerebellar degeneration.

[0294] Primeri za kardiovaskularne bolesti koje mogu da se leče ili spreče, naročito leče, uključuju, bez ograničenja, kardijalnu hipertrofiju, restenozu, aterosklerozu i glomerulonefritis. [0294] Examples of treatable or preventable cardiovascular diseases, particularly treatable, include, without limitation, cardiac hypertrophy, restenosis, atherosclerosis, and glomerulonephritis.

[0295] Primeri za inflamatorne bolesti koje mogu da se leče ili spreče, naročito leče, uključuju, bez ograničenja, inflamaciju povezanu sa aknama, anemiju (npr. aplastična anemija, hemolitička autoimunska anemija), rinitis, astmu, arteritis (npr. poliarteritis, temporalni arteritis, periarteritis nodosa, Takajasuov arteritis), artritis (npr. kristalni artritis, osteoartritis, psorijazni artritis, gihtni artritis, reaktivni artritis, reumatoidni artritis i Rajterov artritis), bolest gornjeg respiratornog trakta, ankilozirajući spondilitis, amilozu, amiotrofnu lateralnu sklerozu, autoimunske bolesti, alergije ili alergijske reakcije, aterosklerozu, bronhitis, bursitis, hronični prostatitis, konjunktivitis, Šagasovu bolest, hroničnu opstruktivnu bolest pluća, divertikulitis, dermatomiozitis, dijabetes (npr. dijabetes melitus tip 1, dijabetes melitus tip 2), kožne poremećaje (npr. psorijaza, ekcem, ekcemske reakcije hipersenzitivnosti, opekotine, dermatitis, [0295] Examples of inflammatory diseases that can be treated or prevented, especially treated, include, without limitation, inflammation associated with acne, anemia (eg, aplastic anemia, hemolytic autoimmune anemia), rhinitis, asthma, arteritis (eg, polyarteritis, temporal arteritis, periarteritis nodosa, Takayasu's arteritis), arthritis (eg, crystalline arthritis, osteoarthritis, psoriatic arthritis, gouty arthritis, reactive arthritis, rheumatoid arthritis and Reiter's arthritis), upper respiratory tract disease, ankylosing spondylitis, amyloidosis, amyotrophic lateral sclerosis, autoimmune diseases, allergies or allergic reactions, atherosclerosis, bronchitis, bursitis, chronic prostatitis, conjunctivitis, Chagas' disease, chronic obstructive pulmonary disease, diverticulitis, dermatomyositis, diabetes (eg diabetes mellitus type 1, diabetes mellitus type 2), skin disorders (eg psoriasis, eczema, eczematous hypersensitivity reactions, burns, dermatitis,

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pruritus (svrab)), endometriozu, Gijen-Bareov sindrom, infekciju, ishemijski srčani udar, Kavasakijevu bolest, glomerulonefritis, gingivitis, hipersenzitivnost, glavobolje (npr. migrenske glavobolje, tenzione glavobolje), ileus (npr postoperativni ileus i ileus prilikom sepse), idiopatsku trombocitopenijsku purpuru, intersticijalni cistitis (sindrom bolne bešike), gastrointestinalni poremećaj (npr. odabran od čira na dvanaestopalačnom crevu, regionalnog enteritisa, divertikulitisa, gastrointestinalnog krvarenja, eozinofilnih gastrointestinalnih poremećaja (npr. eozinofilni ezofagitis, eozinofilni gastritis, eozinofilni gastroenteritis, eozinofilni kolitis), gastritisa, dijareje, gastroezofagealne refluksne bolesti (GORD, ili njen sinonim GERD), inflamatorne bolesti creva (IBD) (npr. Kronova bolest, ulcerozni kolitis, kolagenozni kolitis, limfocitni kolitis, ishemijski kolitis, diverzioni kolitis, Behčetov sindrom, neodređeni kolitis) i inflamatornog sindroma creva (IBS)), lupus, morfeu, mijasteniju gravis, ishemiju miokarda, multiplu sklerozu, nefrotski sindrom, pemfigus vulgaris, pernicioznu anemiju, čir na dvanaestopalačnom crevu, polimiozitis, primarnu bilijarnu cirozu, neuroinflamaciju povezanu sa moždanim poremećajima (npr. Parkinsonova bolest, Hantingtonova bolest i Alchajmerova bolest), prostatitis, hroničnu inflamaciju povezanu sa kranijalnom radijacionom povredom, inflamatornu bolest karlice, reperfuzionu povredu, regionalni enteritis, reumatsku groznicu, sistemski eritemski lupus, sklerodermu, scierodom, sarkoidozu, spondiloartopatije, Šegrenov sindrom, tiroiditis, odbacivanje transplantata, tendonitis, traumu ili povredu (npr., promrzlina, hemijski iritansi, toksini, ožiljci, opekotine, fizička povreda), vaskulitis, vitiligo i Vegenerovu granulomatozu. pruritus (itching)), endometriosis, Guillain-Barré syndrome, infection, ischemic heart attack, Kawasaki disease, glomerulonephritis, gingivitis, hypersensitivity, headaches (e.g. migraine headaches, tension headaches), ileus (e.g. postoperative ileus and ileus in sepsis), idiopathic thrombocytopenic purpura, interstitial cystitis (painful bladder syndrome), gastrointestinal disorder (e.g. selected from duodenal ulcer intestine, regional enteritis, diverticulitis, gastrointestinal bleeding, eosinophilic gastrointestinal disorders (e.g. eosinophilic esophagitis, eosinophilic gastritis, eosinophilic gastroenteritis, eosinophilic colitis), gastritis, diarrhea, gastroesophageal reflux disease (GORD, or its synonym GERD), inflammatory bowel disease (IBD) (e.g. Crohn's disease, ulcerative colitis, collagenous colitis, lymphocytic colitis, ischemic colitis, diverticular colitis, Behçet's syndrome, unspecified colitis) and inflammatory bowel syndrome (IBS)), lupus, morphea, myasthenia gravis, myocardial ischemia, multiple sclerosis, nephrotic syndrome, pemphigus vulgaris, pernicious anemia, duodenal ulcer, polymyositis, primary biliary cirrhosis, neuroinflammation associated with brain disorders (eg, Parkinson's disease, Huntington's disease, and Alzheimer's disease), prostatitis, chronic inflammation associated with cranial radiation injury, pelvic inflammatory disease, reperfusion injury, regional enteritis, rheumatic fever, systemic lupus erythematosus, scleroderma, scierodoma, sarcoidosis, spondyloarthropathies, Sjogren's syndrome, thyroiditis, transplant rejection, tendonitis, trauma or injury (eg, frostbite, chemical irritants, toxins, scars, burns, physical injury), vasculitis, vitiligo, and Wegener's granulomatosis.

[0296] Inflamatorna bolest je naročito akutna inflamatorna bolest (npr. na primer, inflamacija usled infekcije). Inflamatorna bolest je naročito hronična inflamatorna bolest (npr. stanja usled astme, artritis i inflamatorna bolest creva). Jedinjenja takođe mogu biti korisna u lečenju inflamacije povezane sa traumom i neinflamatornom mijalgijom. Jedinjenja takođe mogu biti korisna u lečenju inflamacije povezane sa kancerom. [0296] An inflammatory disease is particularly an acute inflammatory disease (eg, for example, inflammation due to an infection). Inflammatory disease is particularly chronic inflammatory disease (eg conditions due to asthma, arthritis and inflammatory bowel disease). The compounds may also be useful in the treatment of inflammation associated with trauma and non-inflammatory myalgia. The compounds may also be useful in treating inflammation associated with cancer.

[0297] Primeri za autoimunske bolesti koje mogu da se leče ili spreče, naročito leče, uključuju, bez ograničenja, artritis (uključujući reumatoidni artritis, spondiloartopatije, gihtni artritis, degenerativne bolesti zglobova kao što su osteoartritis, sistemski erimatski lupus, Šegrenov sindrom, ankilozirajući spondilitis, nediferencirani spondilitis, Behčetova bolest, hemolitičke autoimunske anemije, amiotrofna lateralna skleroza, amiloza, multipla skleroza, akutni bol u ramenu, psorijaza i juvenilni artritis), astmu, aterosklerozu, osteoporozu, bronhitis, tendonitis, bursitis, bolesti kože (npr. psorijaza, ekcem, ekcemske reakcije hipersenzitivnosti, opekotine, [0297] Examples of autoimmune diseases that can be treated or prevented, in particular treated, include, without limitation, arthritis (including rheumatoid arthritis, spondyloarthropathies, gouty arthritis, degenerative joint diseases such as osteoarthritis, systemic lupus erythematosus, Sjögren's syndrome, ankylosing spondylitis, undifferentiated spondylitis, Behçet's disease, hemolytic autoimmune anemias, amyotrophic lateral sclerosis, amyloidosis, multiple sclerosis, acute shoulder pain, psoriasis and juvenile arthritis), asthma, atherosclerosis, osteoporosis, bronchitis, tendonitis, bursitis, skin diseases (e.g. psoriasis, eczema, eczematous hypersensitivity reactions, burns,

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dermatitis, pruritus (svrab)), enurezu, eozinofilnu bolest, gastrointestinalni poremećaj (npr. izabran od čira na dvanaestopalačnom crevu, regionalnog enteritisa, divertikulitisa, gastrointestinalnog krvarenja, eozinofilni gastrointestinalni poremećaji (npr. eozinofilni ezofagitis, eozinofilni gastritis, eozinofilni gastroenteritis, eozinofilni kolitis), gastritisa, dijareje, gastroezofagealne refluksne bolesti (GORD, ili njen sinonim GERD), inflamatorne bolesti creva (IBD) (npr. Kronova bolest, ulcerozni kolitis, kolagenozni kolitis, limfocitni kolitis, ishemijski kolitis, diverzioni kolitis, Behčetov sindrom, neodređeni kolitis) i inflamatornog sindroma creva (IBS)), i poremećaje koji se ublažavaju gastroprokinetičkim agensom (npr. ileus, postoperativni ileus i ileus prilikom sepse; gastroezofagealna refluksna bolest (GORD, ili njegov sinonim GERD); eozinofilni ezofagitis, gastroparezu kao što je dijabetička gastropareza; intoleranciju na hranu i alrgije na hranu i druge funkcionalne poremećaje creva, kao što je neulcerozna dispepsija (NUD) i nekardijalni bol u grudima (NCCP, uključujući kosto-hondritis)). dermatitis, pruritus (itching)), enuresis, eosinophilic disease, gastrointestinal disorder (e.g., selected from duodenal ulcer, regional enteritis, diverticulitis, gastrointestinal bleeding, eosinophilic gastrointestinal disorders (e.g., eosinophilic esophagitis, eosinophilic gastritis, eosinophilic gastroenteritis, eosinophilic colitis), gastritis, diarrhea, gastroesophageal reflux disease (GORD, or its synonym GERD), inflammatory bowel disease (IBD) (e.g., Crohn's disease, ulcerative colitis, collagenous colitis, lymphocytic colitis, ischemic colitis, diverticular colitis, Behçet's syndrome, indeterminate colitis) and inflammatory bowel syndrome (IBS)), and disorders that are relieved by a gastroprokinetic agent (eg, ileus, postoperative ileus and ileus in sepsis; gastroesophageal reflux disease (GORD, or its synonym GERD); eosinophilic esophagitis, gastroparesis such as diabetic gastroparesis; food intolerance and food allergies and other functional bowel disorders, such as non-ulcer dyspepsia (NUD) and non-cardiac chest pain (NCCP, including costo-chondritis)).

[0298] U konkretnom otelotvorenju, obezbeđeno jedinjenje može biti korisno u reprogramiranju somatskih ćelija, kao što je reprogramiranje somatskih ćelija u matične ćelije. U konkretnom otelotvorenju, obezbeđeno jedinjenje može biti korisno u razvoju germinativnih ćelija, te se tako predviđa da je korisno u oblasti reproduktivne tehnologije i regenerativne medicine. [0298] In a particular embodiment, a provided compound may be useful in reprogramming somatic cells, such as reprogramming somatic cells into stem cells. In a particular embodiment, the provided compound may be useful in the development of germ cells, and thus is expected to be useful in the fields of reproductive technology and regenerative medicine.

[0299] Druge bolesti koje mogu da se leče ili spreče, naročito leče, uključuju, bez ograničenja, infarkt miokarda povezan sa ishemijskom povredom, imunološke povrede, moždani udar, aritmiju, bolesti jetre indukovane toksinima ili povezane sa alkoholom, rinosinuzitis senzitivan na aspirin, cističnu fibrozu, kancerski bol i hematološke poremećaje, na primer, hroničnu anemiju i aplastičnu anemiju. [0299] Other diseases that can be treated or prevented, especially treated, include, without limitation, myocardial infarction associated with ischemic injury, immune injury, stroke, arrhythmia, toxin-induced or alcohol-related liver diseases, aspirin-sensitive rhinosinusitis, cystic fibrosis, cancer pain, and hematologic disorders, for example, chronic anemia and aplastic anemia.

[0300] Jedinjenja iz predmetnog pronalaska takođe mogu imati terapeutske primene u pripremi tumorskih ćelija za radiološku terapiju i hemoterapiju. [0300] The compounds of the present invention may also have therapeutic applications in the preparation of tumor cells for radiological therapy and chemotherapy.

[0301] Stoga jedinjenja iz predmetnog pronalaska mogu da se koriste kao „radiološki senzibilizatori“ i/ili „hemijski senzibilizatori“ ili mogu da se daju u kombinaciji sa drugim „radiološkim senzibilizatorom“ i/ili „hemijskim senzibilizatorom“. [0301] Therefore, the compounds of the present invention can be used as "radiological sensitizers" and/or "chemical sensitizers" or can be administered in combination with another "radiological sensitizer" and/or "chemical sensitizer".

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[0302] Termin „radiološki senzibilizator“, kako se ovde koristi, definiše se kao molekul, poželjno molekul male molekulske mase, koji se primenjuje na životinjama u terapeutski delotvornoj količini kako bi se povećala senzitivnost ćelija na jonizujuće zračenje i/ili da bi se promovisalo lečenje bolesti koje mogu da se leče jonizujućim zračenjem. [0302] The term "radiological sensitizer", as used herein, is defined as a molecule, preferably a low molecular weight molecule, which is administered to animals in a therapeutically effective amount to increase the sensitivity of cells to ionizing radiation and/or to promote the treatment of diseases treatable by ionizing radiation.

[0303] Termin „hemijski senzibilizator“, kako se ovde koristi, definiše se kao molekul, poželjno molekul male molekulske mase, koji se primenjuje na životinjama u terapeutski delotvornoj količini kako bi se povećala senzitivnost ćelija na hemoterapiju i/ili da bi se promovisalo lečenje bolesti koje mogu da se leče hemoterapijom. [0303] The term "chemical sensitizer", as used herein, is defined as a molecule, preferably a low molecular weight molecule, that is administered to animals in a therapeutically effective amount to increase the sensitivity of cells to chemotherapy and/or to promote the treatment of diseases amenable to chemotherapy.

[0304] U literaturi je predloženo nekoliko mehanizama za režim delovanja radiološkog senzibilizatora, uključujući: radiološke senzibilizatore hipoksijskih ćelija (npr. jedinjenja 2-nitroimidazola i jedinjenja benzotriazin dioksida) koji oponašaju kiseonik ili se alternativno ponašaju kao bioreduktivni agensi prilikom hipoksije; radiološke senzibilizatore nehipoksijskih ćelija (npr. halogenovani pirimidini) koji mogu biti analozi DNK baza i poželjno se inkorporiraju u DNK kancerskih ćelija, te tako promovišu radijacijom indukovanu razgradnju molekula DNK i/ili sprečavaju normalne mehanizme popravke DNK; i različiti drugi mogući mehanizmi delovanja su predloženi za radiološke senzibilizatore prilikom lečenja bolesti. [0304] Several mechanisms for the radiological sensitizer mode of action have been proposed in the literature, including: radiological sensitizers of hypoxic cells (eg, 2-nitroimidazole compounds and benzotriazine dioxide compounds) that mimic oxygen or alternatively act as bioreductive agents during hypoxia; radiological sensitizers of non-hypoxic cells (eg, halogenated pyrimidines) which may be analogs of DNA bases and preferentially incorporate into the DNA of cancer cells, thus promoting radiation-induced degradation of DNA molecules and/or preventing normal DNA repair mechanisms; and various other possible mechanisms of action have been proposed for radiological sensitizers in the treatment of disease.

[0305] Brojni protokoli za lečenje kancera trenutno koriste radiološke senzibilizatore zajedno sa rendgenskim zračenjem. Primeri za rendgenski aktivirane radiološke senzibilizatore uključuju, ali nisu ograničeni na sledeće: metronidazol, mizonidazol, dezmetilmizonidazol, pimonidazol, etanidazol, nimorazol, mitomicin C, RSU 1069, SR 4233, EO9, [0305] A number of cancer treatment protocols currently use radiological sensitizers in conjunction with X-rays. Examples of X-ray activated radiological sensitizers include, but are not limited to, metronidazole, misonidazole, desmethylmisonidazole, pimonidazole, etanidazole, nimorazole, mitomycin C, RSU 1069, SR 4233, EO9,

[0306] RB 6145, nikotinamid, 5-brom dezoksiuridin (BUdR), 5- jod dezoksiuridin (IUdR), brom dezoksicitidin, fluor dezoksiuridin (FudR), hidroksiureu, cisplatin i terapeutski delotvorne analoge i derivate navedenog. [0306] RB 6145, nicotinamide, 5-bromo deoxyuridine (BUdR), 5-iodo deoxyuridine (IUdR), bromo deoxycytidine, fluoro deoxyuridine (FudR), hydroxyurea, cisplatin and therapeutically effective analogues and derivatives of the above.

[0307] Fotodinamička terapija (PDT) kancera koristi vidljivo svetlo kao aktivator radijacije agensa za senzibilizaciju. Primeri za fotodinamičke radiološke senzibilizatore uključuju sledeće, bez ograničenja: derivate hematoporfirina, Photofrin, derivate benzoporfirina, kalaj etioporfirin, feoborbid-a, bakteriohlorofil-a, naftalocijanine, ftalocijanine, cink ftalocijanin i terapeutski delotvorne analoge i derivate navedenog. [0307] Photodynamic therapy (PDT) of cancer uses visible light as a radiation activator of the sensitizing agent. Examples of photodynamic radiological sensitizers include the following, without limitation: hematoporphyrin derivatives, Photofrin, benzoporphyrin derivatives, tin etioporphyrin, pheoborbide-a, bacteriochlorophyll-a, naphthalocyanines, phthalocyanines, zinc phthalocyanine, and therapeutically effective analogs and derivatives thereof.

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[0308] Radiološki senzibilizatori mogu da se primenjuju zajedno sa terapeutski delotvornom količinom jednog ili više drugih jedinjenja, uključujući, bez ograničenja: jedinjenja koja promovišu inkorporaciju radioloških senzibilizatora u ciljne ćelije; jedinjenja koja kontrolišu dotok lekova, hranljivih materija i/ili kiseonika u ciljne ćelije; hemoterapeutske agense koji deluju na tumor uz dodatno zračenje ili bez njega; ili druga terapeutski delotvorna jedinjenja za lečenje kancera ili drugih bolesti. [0308] The radiological sensitizers may be administered together with a therapeutically effective amount of one or more other compounds, including, without limitation: compounds that promote the incorporation of the radiological sensitizers into target cells; compounds that control the flow of drugs, nutrients and/or oxygen to target cells; chemotherapeutic agents acting on the tumor with or without additional radiation; or other therapeutically effective compounds for the treatment of cancer or other diseases.

[0309] Hemijski senzibilizatori mogu da se primenjuju zajedno sa terapeutski delotvornom količinom jednog ili više drugih jedinjenja, uključujući, bez ograničenja: jedinjenja koja promovišu inkorporaciju hemijskih senzibilizatora u ciljne ćelije; jedinjenja koja kontrolišu dotok lekova, hranljivih materija i/ili kiseonika u ciljne ćelije; hemoterapeutske agense koji deluju na tumor, ili druga terapeutski delotvorna jedinjenja za lečenje kancera ili drugih bolesti. Pokazalo se da su antagonisti kalcijuma, na primer verapamil, korisni u kombinaciji sa antineoplastičnim agensima za uspostavljanje hemosenzitivnosti u tumorskim ćelijama koje su otporne na prihvaćene hemoterapeutske agense, i za povećanje delotvornosti takvih jedinjenja kod maligniteta osetljivih na lek. [0309] The chemical sensitizers may be administered together with a therapeutically effective amount of one or more other compounds, including, without limitation: compounds that promote incorporation of the chemical sensitizers into target cells; compounds that control the flow of drugs, nutrients and/or oxygen to target cells; chemotherapeutic agents that act on a tumor, or other therapeutically effective compounds for the treatment of cancer or other diseases. Calcium antagonists, for example verapamil, have been shown to be useful in combination with antineoplastic agents to induce chemosensitivity in tumor cells resistant to accepted chemotherapeutic agents, and to enhance the efficacy of such compounds in drug-sensitive malignancies.

[0310] Jedinjenja iz predmetnog pronalaska takođe mogu da smanjuju rizik od ponovne pojave kancera. [0310] Compounds of the present invention may also reduce the risk of cancer recurrence.

[0311] Pronalazak se odnosi na jedinjenja formule (I) i njihove farmaceutski prihvatljive adicione soli i solvate, za upotrebu kao lek. [0311] The invention relates to compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates, for use as medicine.

[0312] Pronalazak se odnosi na jedinjenja formule (I) i njihove farmaceutski prihvatljive adicione soli i solvate, za upotrebu u inhibiciji aktivnosti PRMT5. [0312] The invention relates to compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates, for use in inhibiting PRMT5 activity.

[0313] Jedinjenja iz predmetnog pronalaska mogu biti „antikancerski agensi“, pri čemu taj termin obuhvata „agense protiv rasta tumorskih ćelija“ i „antineoplastične agense“. [0313] The compounds of the present invention may be "anticancer agents", which term includes "antitumor cell growth agents" and "antineoplastic agents".

[0314] Pronalazak se odnosi na jedinjenja formule (I) i njihove farmaceutski prihvatljive adicione soli i solvate, za upotrebu u lečenju prethodno navedenih bolesti. [0314] The invention relates to compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates, for use in the treatment of the aforementioned diseases.

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[0315] Pronalazak se odnosi na jedinjenja formule (I) i njihove farmaceutski prihvatljive adicione soli i solvate, za lečenje ili prevenciju, naročito za lečenje, navedenih bolesti. [0315] The invention relates to compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates, for the treatment or prevention, especially for the treatment, of the mentioned diseases.

[0316] Pronalazak se odnosi na jedinjenja formule (I) i njihove farmaceutski prihvatljive adicione soli i solvate, za lečenje ili prevenciju, naročito za lečenje, bolesti ili stanja posredovanih sa PRMT5. [0316] The invention relates to compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates, for the treatment or prevention, in particular for the treatment, of diseases or conditions mediated by PRMT5.

[0317] Pronalazak se odnosi na jedinjenja formule (I) i njihove farmaceutski prihvatljive adicione soli i solvate, za proizvodnju leka. [0317] The invention relates to compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates, for the production of medicine.

[0318] Pronalazak se odnosi na jedinjenja formule (I) i njihove farmaceutski prihvatljive adicione soli i solvate, za proizvodnju leka za inhibiciju PRMT5. [0318] The invention relates to compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates, for the production of a drug for PRMT5 inhibition.

[0319] Pronalazak se odnosi na jedinjenja formule (I) i njihove farmaceutski prihvatljive adicione soli i solvate, za proizvodnju leka za lečenje ili prevenciju, naročito za lečenje, bilo koje bolesti prethodno navedene u ovom tekstu. [0319] The invention relates to compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates, for the production of a drug for the treatment or prevention, in particular for the treatment, of any disease previously mentioned in this text.

[0320] Pronalazak se odnosi na jedinjenja formule (I) i njihove farmaceutski prihvatljive adicione soli i solvate, za proizvodnju leka za lečenje bilo koje bolesti prethodno navedene u ovom tekstu. [0320] The invention relates to compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates, for the production of a drug for the treatment of any of the diseases previously mentioned in this text.

[0321] Pronalazak se odnosi na jedinjenja formule (I) i njihove farmaceutski prihvatljive adicione soli i solvate, koja mogu da se primenjuju na sisarima, poželjno ljudima, za lečenje ili prevenciju bilo koje bolesti prethodno navedene u ovom tekstu. [0321] The invention relates to compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates, which can be applied to mammals, preferably humans, for the treatment or prevention of any disease previously mentioned in this text.

[0322] Imajući u vidu korisnost jedinjenja formule (I) i njihovih farmaceutski prihvatljivih adicionih soli i solvata, obezbeđen je postupak za lečenje toplokrvnih životinja, uključujući ljude, obolelih od bilo koje bolesti prethodno navedene u ovom tekstu, ili postupak za prevenciju oboljevanja toplokrvnih životinja, uključujući ljude. [0322] In view of the usefulness of the compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates, a method is provided for the treatment of warm-blooded animals, including humans, suffering from any of the diseases previously mentioned herein, or a method for the prevention of disease in warm-blooded animals, including humans.

[0323] Navedeni postupci obuhvataju primenu, tj. sistemsku ili topikalnu primenu, poželjno oralnu primenu, delotvorne količine jedinjenja formule (I) ili njegove farmaceutski prihvatljive adicione soli ili solvata, na toplokrvnim životinjama, uključujući ljude. [0323] The mentioned procedures include application, i.e. systemic or topical administration, preferably oral administration, of an effective amount of a compound of formula (I) or a pharmaceutically acceptable addition salt or solvate thereof, to warm-blooded animals, including humans.

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[0324] Osobe sa veštinama u lečenju takvih bolesti mogu da odrede delotvornu terapeutsku dnevnu količinu iz rezultata testova koji su prikazani u nastavku. Delotvorna terapeutska dnevna količina bi bila od oko 0,005 mg/kg do 50 mg/kg, naročito 0,01 mg/kg do 50 mg/kg telesne težine, konkretnije od 0,01 mg/kg do 25 mg/kg telesne težine, poželjno od oko 0,01 mg/kg do oko 15 mg/kg, poželjnije od oko 0,01 mg/kg do oko 10 mg/kg, još poželjnije od oko 0,01 mg/kg do oko 1 mg/kg, najpoželjnije od oko 0,05 mg/kg do oko 1 mg/kg telesne težine. Naročito delotvorna terapeutska dnevna količina može biti od oko 0,01 do 1,00 g dva puta dnevno (BID), konkretnije 0,30 do 0,85 g BID, još konkretnije 0,40 g BID. Količina jedinjenja prema predmetnom pronalasku, koje se ovde naziva i aktivni sastojak, koja je potrebna za postizanje terapeutskog dejstva će naravno varirati od slučaja do slučaja, na primer, u zavisnosti od konkretnog jedinjenja, načina primene, starosti i stanja primaoca, i konkretnog poremećaja ili bolesti koji se leče. [0324] Persons skilled in the treatment of such diseases can determine an effective therapeutic daily amount from the results of the tests shown below. An effective therapeutic daily amount would be from about 0.005 mg/kg to 50 mg/kg, particularly 0.01 mg/kg to 50 mg/kg body weight, more specifically from 0.01 mg/kg to 25 mg/kg body weight, preferably from about 0.01 mg/kg to about 15 mg/kg, more preferably from about 0.01 mg/kg to about 10 mg/kg, even more preferably from about 0.01 mg/kg to about 1 mg/kg, most preferably from about 0.05 mg/kg to about 1 mg/kg of body weight. A particularly effective therapeutic daily amount may be from about 0.01 to 1.00 g twice daily (BID), more specifically 0.30 to 0.85 g BID, more specifically 0.40 g BID. The amount of a compound of the present invention, also referred to herein as an active ingredient, required to achieve a therapeutic effect will of course vary from case to case, for example, depending on the particular compound, the route of administration, the age and condition of the recipient, and the particular disorder or disease being treated.

[0325] Postupak lečenja takođe može da obuhvata primenu aktivnog sastojka u režimu od jednog do četiri unosa dnevno. U ovim postupcima lečenja, jedinjenja prema pronalasku su poželjno formulisana pre primene. Kao što je ovde u nastavku opisano, odgovarajuće farmaceutske formulacije su pripremljene poznatim procedurama koristeći dobro poznate i lako dostupne sastojke. [0325] The method of treatment may also include administration of the active ingredient in a regimen of one to four intakes per day. In these methods of treatment, the compounds of the invention are preferably formulated prior to administration. As described hereinbelow, suitable pharmaceutical formulations are prepared by known procedures using well known and readily available ingredients.

[0326] Jedinjenja iz predmetnog pronalaska, koja bi bila pogodna za lečenje ili prevenciju kancera ili stanja povezanih s kancerom, mogu da se primene samostalno ili u kombinaciji sa jednim ili više dodatnih terapeutskih agensa. Kombinovana terapija obuhvata primenu jedne farmaceutske dozne formulacije koja sadrži jedinjenje formule (I), njegovu farmaceutski prihvatljivu adicionu so ili solvat, i jedan ili više dodatnih terapeutskih agensa, kao i primenu jedinjenja formule (I), njegove farmaceutski prihvatljive adicione soli ili solvata, i svakog dodatnog terapeutskog agensa u zasebnoj farmaceutskoj doznoj formulaciji. Na primer, jedinjenje formule (I), njegova farmaceutski prihvatljiva adiciona so ili solvat, i terapeutski agens mogu da se primene na pacijentu zajedno u jednoj oralnoj doznoj kompoziciji kao što je tableta ili kapsula, ili svaki agens može da se primeni u zasebnim oralnim doznim formulacijama. [0326] Compounds of the present invention, which would be suitable for the treatment or prevention of cancer or cancer-related conditions, can be administered alone or in combination with one or more additional therapeutic agents. Combination therapy includes the administration of a single pharmaceutical dosage formulation containing a compound of formula (I), its pharmaceutically acceptable addition salt or solvate, and one or more additional therapeutic agents, as well as the administration of a compound of formula (I), its pharmaceutically acceptable addition salt or solvate, and each additional therapeutic agent in a separate pharmaceutical dosage formulation. For example, a compound of formula (I), a pharmaceutically acceptable addition salt or solvate thereof, and a therapeutic agent may be administered to a patient together in a single oral dosage composition such as a tablet or capsule, or each agent may be administered in separate oral dosage formulations.

[0327] Iako je moguće da se aktivni sastojak primenjuje samostalno, poželjno je da se predstavi u vidu farmaceutske kompozicije. [0327] Although it is possible for the active ingredient to be administered alone, it is preferable to present it in the form of a pharmaceutical composition.

1 1 1 1

[0328] Shodno tome, predmetni pronalazak dalje obezbeđuje farmaceutsku kompoziciju i, u vidu aktivnog sastojka, terapeutski delotvornu količinu jedinjenja formule (I), njegove farmaceutski prihvatljive adicione soli ili solvata. [0328] Accordingly, the present invention further provides a pharmaceutical composition and, in the form of an active ingredient, a therapeutically effective amount of a compound of formula (I), a pharmaceutically acceptable addition salt or solvate thereof.

[0329] Shodno tome, predmetni pronalazak dalje obezbeđuje farmaceutsku kompoziciju koja sadrži farmaceutski prihvatljiv nosač i, kao aktivni sastojak, terapeutski delotvornu količinu jedinjenja formule (I), njegove farmaceutski prihvatljive adicione soli ili solvata. [0329] Accordingly, the present invention further provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and, as an active ingredient, a therapeutically effective amount of a compound of formula (I), a pharmaceutically acceptable addition salt or solvate thereof.

[0330] Nosač ili razblaživač mora biti „prihvatljiv“ u smislu da je kompatibilan sa drugim sastojcima kompozicije i nije štetan po osobe koje ga primaju. [0330] The carrier or diluent must be "acceptable" in the sense that it is compatible with the other ingredients of the composition and is not harmful to the recipient.

[0331] Radi lakoće primene, predmetna jedinjenja mogu biti formulisana u različite farmaceutske oblike u svrhu primene. Jedinjenja prema pronalasku, naročito jedinjenja formule (I) i njegove farmaceutski prihvatljive adicione soli i solvati, ili bilo koja njihova podgrupa ili kombinacija, mogu da se formulišu u različite farmaceutske oblike u svrhu primene. Kao odgovarajuće kompozicije mogu da se navedu sve kompozicije koje se uobičajeno koriste za sistemsku primenu lekova. [0331] For ease of administration, the subject compounds may be formulated into various pharmaceutical forms for the purpose of administration. The compounds according to the invention, especially the compounds of formula (I) and its pharmaceutically acceptable addition salts and solvates, or any subgroup or combination thereof, can be formulated into various pharmaceutical forms for the purpose of administration. All compositions that are commonly used for systemic administration of drugs can be mentioned as suitable compositions.

[0332] Za pripremu farmaceutskih kompozicija iz ovog pronalaska, delotvorna količina konkretnog jedinjenja kao aktivnog sastojka se kombinuje u bliskoj smeši sa farmaceutski prihvatljivim nosačem, pri čemu nosač može imati širok raspon oblika u zavisnosti od oblika preparata koji je poželjan za primenu. Farmaceutske kompozicije su poželjne u jediničnom doznom obliku koji je pogodan, naročito, za oralnu, rektalnu, perkutanu primenu, primenu putem parenteralne injekcije ili putem inhalacije. Na primer, kod pripreme kompozicija u oralnom doznom obliku, može da se koristi bilo koji od uobičajenih farmaceutskih medijuma kao što su, na primer, voda, glikoli, ulja, alkoholi, i slično, u slučaju tečnih oralnih preparata kao što su suspenzije, sirupi, eliksiri, emulzije i rastvori; ili čvrsti nosači kao što su skrobovi, šećeri, kaolin, razblaživači, lubrikansi, vezivači, dezintegransi, i slično, u slučaju praškova, pilula, kapsula i tableta. Zbog svoje lakoće primene, tablete i kapsule predstavljaju najpogodnije oralne jedinične dozne oblike u kojima se očigledno koriste čvrsti farmaceutski nosači. Za parenteralne kompozicije, nosač će obično da obuhvata sterilnu vodu, barem velikim delom, mada drugi sastojci, na primer, za poboljšanje rastvorljivosti, mogu biti uključeni. Mogu da se pripreme, na primer, injektabilni rastvori u kojima nosač uključuje fiziološki rastvor, rastvor glukoze ili smešu fiziološkog rastvora i rastvora glukoze. Injektabilni rastvori [0332] For the preparation of pharmaceutical compositions of this invention, an effective amount of the particular compound as an active ingredient is combined in close admixture with a pharmaceutically acceptable carrier, wherein the carrier can have a wide range of forms depending on the form of the preparation that is desired for use. The pharmaceutical compositions are preferably in a unit dosage form suitable, in particular, for oral, rectal, percutaneous administration, administration by parenteral injection or by inhalation. For example, in the preparation of compositions in oral dosage form, any of the usual pharmaceutical media can be used such as, for example, water, glycols, oils, alcohols, and the like, in the case of liquid oral preparations such as suspensions, syrups, elixirs, emulsions and solutions; or solid carriers such as starches, sugars, kaolin, diluents, lubricants, binders, disintegrants, and the like, in the case of powders, pills, capsules and tablets. Because of their ease of administration, tablets and capsules are the most convenient oral unit dosage forms in which solid pharmaceutical carriers are obviously used. For parenteral compositions, the vehicle will usually comprise sterile water, at least in large part, although other ingredients, for example to improve solubility, may be included. For example, injectable solutions can be prepared in which the carrier includes saline, glucose, or a mixture of saline and glucose. Injectable solutions

1 2 1 2

koji sadrže jedinjenje formule (I), njegovu farmaceutski prihvatljivu adicionu so ili solvat mogu da se formulišu u ulju radi produženog dejstva. Odgovarajuća ulja za ovu svrhu su, na primer, kikirikijevo ulje, susamovo ulje, ulje semenki pamuka, kukuruzno ulje, sojino ulje, sintetički glicerol estri masnih kiselina dugog lanca, i smeše ovih i drugih ulja. Takođe mogu da se pripreme injektabilne suspenzije, i tada mogu da se koriste odgovarajući tečni nosači, suspendujući agensi, i slično. Takođe su uključeni čvrsti oblici preparata koji su predviđeni za pretvaranje, neposredno pre upotrebe, u tečne oblike preparata. U kompozicijama koje su pogodne za perkutanu primenu, nosač opciono sadrži agens za pojačavanje penetracije i/ili odgovarajući kvašljivac, opciono u kombinaciji sa malim udelom odgovarajućih aditiva bilo koje vrste, pri čemu ti aditivi nemaju značajno štetno dejstvo na kožu. Navedeni aditivi mogu olakšati primenu na koži i/ili mogu biti korisni za pripremanje željenih kompozicija. Te kompozicije mogu da se primene na različite načine, npr. kao transdermalni flaster, kao rastvor za nanošenje, kao melem. Kisele ili bazne adicione soli jedinjenja formule (I) pogodnije su za pripremu vodenih kompozicija usled svoje povećane rastvorljivosti u vodi u odnosu na odgovarajući bazni ili kiseli oblik. containing a compound of formula (I), a pharmaceutically acceptable addition salt or solvate thereof may be formulated in oil for prolonged action. Suitable oils for this purpose are, for example, peanut oil, sesame oil, cottonseed oil, corn oil, soybean oil, synthetic glycerol esters of long chain fatty acids, and mixtures of these and other oils. Injectable suspensions can also be prepared, in which case suitable liquid carriers, suspending agents, and the like can be used. Also included are solid forms of the preparation that are intended to be converted, immediately before use, into liquid forms of the preparation. In compositions suitable for percutaneous administration, the carrier optionally contains a penetration-enhancing agent and/or a suitable wetting agent, optionally in combination with a small proportion of suitable additives of any kind, such additives having no significant adverse effect on the skin. Said additives can facilitate the application on the skin and/or can be useful for preparing the desired compositions. These compositions can be applied in different ways, e.g. as a transdermal patch, as a solution for application, as an ointment. Acidic or basic addition salts of compounds of formula (I) are more suitable for the preparation of aqueous compositions due to their increased solubility in water compared to the corresponding basic or acidic form.

[0333] Posebno je pogodno da se prethodno navedene farmaceutske kompozicije formulišu u jediničnom doznom obliku radi lakoće primene i uniformnosti doze. Jedinični dozni oblik, kako se ovde koristi, odnosi se na fizički diskretne jedinice koje su pogodne kao pojedinačne doze, pri čemu svaka jedinica sadrži prethodno utvrđenu količinu aktivnog sastojka za koju je izračunato da daje željeno terapeutsko dejstvo u asocijaciji sa potrebnim farmaceutskim nosačem. Primeri za takve jedinične dozne oblike su tablete (uključujući podeljene ili obložene tablete), kapsule, pilule, paketi praškova, pločice, supozitorije, injektabilni rastvori ili suspenzije, i slično, i njihovi razdeljeni umnošci. [0333] It is particularly convenient to formulate the aforementioned pharmaceutical compositions in unit dosage form for ease of administration and uniformity of dosage. Unit dosage form, as used herein, refers to physically discrete units suitable as single doses, each unit containing a predetermined amount of active ingredient calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. Examples of such unit dosage forms are tablets (including divided or coated tablets), capsules, pills, powder packets, tablets, suppositories, injectable solutions or suspensions, and the like, and divided multiples thereof.

[0334] Kako bi se povećala rastvorljivost i/ili stabilnost jedinjenja formule (I) i njihovih farmaceutski prihvatljivih adicionih soli i solvata u farmaceutskim kompozicijama, može biti korisno da se koriste α-, β- ili γ-ciklodekstrini ili njihovi derivati, naročito hidroksialkil supstituisani ciklodekstrini, npr.2-hidroksipropil-β-ciklodekstrin ili sulfobutil-β-ciklodekstrin. Takođe, korastvarači kao što su alkoholi mogu da poboljšaju rastvorljivost i/ili stabilnost jedinjenja prema predmetnom pronalasku u farmaceutskim kompozicijama. [0334] In order to increase the solubility and/or stability of compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates in pharmaceutical compositions, it may be useful to use α-, β- or γ-cyclodextrins or their derivatives, especially hydroxyalkyl substituted cyclodextrins, e.g. 2-hydroxypropyl-β-cyclodextrin or sulfobutyl-β-cyclodextrin. Also, co-solvents such as alcohols can improve the solubility and/or stability of the compounds of the present invention in pharmaceutical compositions.

[0335] U zavisnosti od načina primene, farmaceutska kompozicija će poželjno sadržati od 0,05 do 99% masenih, poželjnije od 0,1 do 70% masenih, još poželjnije od 0,1 do 50% masenih [0335] Depending on the method of application, the pharmaceutical composition will preferably contain from 0.05 to 99% by mass, more preferably from 0.1 to 70% by mass, even more preferably from 0.1 to 50% by mass

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jedinjenja formule (I), njegove farmaceutski prihvatljive adicione soli ili solvata, i od 1 do 99,95% masenih, poželjnije od 30 do 99,9% masenih, još poželjnije od 50 do 99,9% masenih farmaceutski prihvatljivog nosača, pri čemu se svi procenti zasnivaju na ukupnoj težini kompozicije. compounds of formula (I), its pharmaceutically acceptable addition salts or solvates, and from 1 to 99.95% by weight, more preferably from 30 to 99.9% by weight, even more preferably from 50 to 99.9% by weight of a pharmaceutically acceptable carrier, where all percentages are based on the total weight of the composition.

[0336] Kao još jedan aspekt predmetnog pronalaska, predviđena je kombinacija jedinjenja iz predmetnog pronalaska sa drugim antikancerskim agensom, naročito za upotrebu kao lek, konkretnije za upotrebu u lečenju kancera ili srodnih bolesti. [0336] As another aspect of the present invention, a combination of the compound of the present invention with another anticancer agent is provided, especially for use as a medicine, more specifically for use in the treatment of cancer or related diseases.

[0337] U lečenju prethodnih stanja, jedinjenja iz pronalaska mogu pogodno da se koriste u kombinaciji sa preusmeravanjem imunoloških ćelija na bazi antitela, na primer, preusmeravanjem T-ćelija/neutrofila. To, na primer, može da se ostvari upotrebom bispecifičnih monoklonskih antitela ili veštačkih receptora T-ćelija. [0337] In the treatment of the above conditions, the compounds of the invention may conveniently be used in combination with antibody-based immune cell redirection, for example, T-cell/neutrophil redirection. This can, for example, be achieved by using bispecific monoclonal antibodies or artificial T-cell receptors.

[0338] U lečenju prethodnih stanja, jedinjenja iz pronalaska mogu pogodno da se koriste u kombinaciji sa jednim ili više drugih medicinskih agensa, konkretnije, sa drugim antikancerskim agensima ili adjuvansima u terapiji kancera. Primeri antikancerskih agensa ili adjuvansa (pomoćni agensi u terapiji) uključuju, ali nisu ograničeni na: [0338] In the treatment of the foregoing conditions, the compounds of the invention may conveniently be used in combination with one or more other medicinal agents, more specifically, with other anticancer agents or adjuvants in cancer therapy. Examples of anticancer agents or adjuvants include, but are not limited to:

• koordinaciona jedinjenja platine, na primer, cisplatin opciono kombinovan sa amifostinom, karboplatinom ili oksaliplatinom; • coordination platinum compounds, for example, cisplatin optionally combined with amifostine, carboplatin or oxaliplatin;

• jedinjenja taksana, na primer, paklitaksel, čestice paklitaksela vezane za protein (Abraxane™) ili docetaksel; • taxane compounds, for example, paclitaxel, protein-bound paclitaxel particles (Abraxane™) or docetaxel;

• inhibitore topoizomeraze I kao što su jedinjenja kamptotecina, na primer, irinotekan, SN-38, topotekan, topotekan hcl; • topoisomerase I inhibitors such as camptothecin compounds, for example, irinotecan, SN-38, topotecan, topotecan hcl;

• inhibitore topoizomeraze II kao što su antitumorski derivati epipodofilotoksina ili podofilotoksina, na primer, etopozid, etopozid fosfat ili tenipozid; • topoisomerase II inhibitors such as antitumor derivatives of epipodophyllotoxin or podophyllotoxin, for example, etoposide, etoposide phosphate or teniposide;

• antitumorske vinka alkaloide, na primer, vinblastin, vinkristin ili vinorelbin; • antitumor vinca alkaloids, for example, vinblastine, vincristine or vinorelbine;

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antitumorske nukleozidne derivate, na primer, 5-fluoruracil, leukovorin, gemcitabin, gemcitabin hcl, kapecitabin, kladribin, fludarabin, nelarabin; antitumor nucleoside derivatives, for example, 5-fluorouracil, leucovorin, gemcitabine, gemcitabine hcl, capecitabine, cladribine, fludarabine, nelarabine;

alkilujuće agense kao što su azotni iperit ili nitrozourea, na primer, ciklofosfamid, hlorambucil, karmustin, tiotep, mefalan (melfalan), lomustin, altretamin, busulfan, dakarbazin, estramustin, ifosfamid opciono u kombinaciji sa mesnom, pipobromanom, prokarbazinom, streptozocinom, temozolomidom, uracilom; alkylating agents such as nitrogen mustard or nitrosourea, for example, cyclophosphamide, chlorambucil, carmustine, thiotep, mephalan (melphalan), lomustine, altretamine, busulfan, dacarbazine, estramustine, ifosfamide optionally in combination with mesna, pipobroman, procarbazine, streptozocin, temozolomide, uracil;

antitumorske derivate antraciklina, na primer, daunorubicin, doksorubicin opciono u kombinaciji sa deksrazoksanom, doksilom, idarubicinom, mitoksantronom, epirubicinom, epirubicinom hcl, valrubicinom; antitumor anthracycline derivatives, for example, daunorubicin, doxorubicin optionally in combination with dexrazoxane, doxil, idarubicin, mitoxantrone, epirubicin, epirubicin hcl, valrubicin;

molekule koji ciljaju IGF-1 receptor, na primer, pikropodofilin; molecules that target the IGF-1 receptor, for example, picropodophyllin;

derivate tetrakarcina, na primer, tetrokarcin A; tetracarcin derivatives, for example, tetrocarcin A;

glukokortikoide, na primer, prednizon; glucocorticoids, for example, prednisone;

antitela, na primer, trastuzumab (HER2 antitelo), rituksimab (CD20 antitelo), gemtuzumab, gemtuzumab ozogamicin, cetuksimab, pertuzumab, bevacizumab, alemtuzumab, ekulizumab, ibritumomab tiuksetan, nofetumomab, panitumumab, tozitumomab, CNTO 328; antibodies, for example, trastuzumab (HER2 antibody), rituximab (CD20 antibody), gemtuzumab, gemtuzumab ozogamicin, cetuximab, pertuzumab, bevacizumab, alemtuzumab, eculizumab, ibritumomab tiuxetan, nofetumomab, panitumumab, tozitumomab, CNTO 328;

antagoniste receptora estrogena ili selektivne modulatore receptora estrogena ili inhibitore sinteze estrogena, na primer, tamoksifen, fulvestrant, toremifen, droloksifen, faslodeks, raloksifen ili letrozol; estrogen receptor antagonists or selective estrogen receptor modulators or estrogen synthesis inhibitors, for example, tamoxifen, fulvestrant, toremifene, droloxifene, faslodex, raloxifene or letrozole;

inhibitore aromataze, kao što je eksemestan, anastrozol, letrazol, testolakton i vorozol; aromatase inhibitors, such as exemestane, anastrozole, letrazole, testolactone and vorozole;

diferencirajuće agense kao što su retinoidi, vitamin D ili retinolna kiselina, i agense koji blokiraju metabolizam retinolne kiseline (RAMBA), na primer, akutan; differentiating agents such as retinoids, vitamin D or retinoic acid, and agents that block the metabolism of retinoic acid (RAMBA), for example, acute;

inhibitore DNK metil transferaze, na primer, azacitidin ili decitabin; DNA methyl transferase inhibitors, for example, azacitidine or decitabine;

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antifolate, na primer, premetreksed dinatrijum; antifolates, for example, premetrexed disodium;

antibiotike, na primer, antinomicin D, bleomicin, mitomicin C, daktinomicin, karminomicin, daunomicin, levamizol, plikamicin, mitramicin; antibiotics, for example, antinomycin D, bleomycin, mitomycin C, dactinomycin, carminomycin, daunomycin, levamisole, plicamycin, mithramycin;

antimetabolite, na primer, klofarabin, aminopterin, citozin arabinozid ili metotreksat, azacitidin, citarabine, floksuridin, pentostatin, tioguanin; antimetabolites, for example, clofarabine, aminopterin, cytosine arabinoside or methotrexate, azacitidine, cytarabine, floxuridine, pentostatin, thioguanine;

agense koji indukuju apoptozu i antiangiogene agense kao što su Bcl-2 inhibitori, na primer, YC 137, BH 312, ABT 737, gosipol, HA 14-1, TW 37 ili dekanska kiselina; apoptosis inducing agents and antiangiogenic agents such as Bcl-2 inhibitors, for example, YC 137, BH 312, ABT 737, gossypol, HA 14-1, TW 37 or decanoic acid;

agense koji vezuju tubulin, na primer, kombrestatin, kolhicini ili nokodazol; tubulin-binding agents, for example combrestatin, colchicines or nocodazole;

inhibitore kinaze (npr. inhibitori EGFR (receptor epitelnog faktora rasta), MTKI (višeciljni inhibitori kinaze), inhibitori mTOR), na primer, flavoperidol, imatinib mezilat, erlotinib, gefitinib, dasatinib, lapatinib, lapatinib ditozilat, sorafenib, sunitinib, sunitinib maleat, temsirolimus; kinase inhibitors (eg, EGFR (epithelial growth factor receptor) inhibitors, MTKIs (multi-targeted kinase inhibitors), mTOR inhibitors), eg, flavoperidol, imatinib mesylate, erlotinib, gefitinib, dasatinib, lapatinib, lapatinib ditosylate, sorafenib, sunitinib, sunitinib maleate, temsirolimus;

inhibitore farnezil transferaze, na primer, tipifarnib; farnesyl transferase inhibitors, for example, tipifarnib;

inhibitore histon deacetilaze (HDAC), na primer, natrijum butirat, suberoil anilidna hidroksaminska kiselina (SAHA), depsipeptid (FR 901228), NVP-LAQ824, R306465, JNJ-26481585, trihostatin A, vorinostat; histone deacetylase (HDAC) inhibitors, for example, sodium butyrate, suberoyl anilide hydroxamic acid (SAHA), depsipeptide (FR 901228), NVP-LAQ824, R306465, JNJ-26481585, trichostatin A, vorinostat;

Inhibitore puta ubikvitin-proteazoma, na primer, PS-341, MLN .41 ili bortezomib; Inhibitors of the ubiquitin-proteasome pathway, for example, PS-341, MLN .41 or bortezomib;

Yondelis; Yondelis;

inhibitore telomeraze, na primer, telomestatin; telomerase inhibitors, for example, telomestatin;

inhibitore matrične metaloproteinaze, na primer, batimastat, marimastat, prinostat ili metastat. matrix metalloproteinase inhibitors, for example, batimastat, marimastat, prinostat or metastat.

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rekombinantne interleukine, na primer, aldesleukin, denileukin diftitoks, interferon alfa 2a, interferon alfa 2b, peginterferon alfa 2b recombinant interleukins, for example, aldesleukin, denileukin diphtitox, interferon alfa 2a, interferon alfa 2b, peginterferon alfa 2b

inhibitore MAPK MAPK inhibitors

Retinoide, na primer, alitretinoin, beksaroten, tretinoin Retinoids, for example, alitretinoin, bexarotene, tretinoin

arsenik trioksid arsenic trioxide

asparaginazu asparaginase

steroide, na primer, dromostanolon propionat, megestrol acetat, nandrolon (dekanoat, fenpropionat), deksametazon steroids eg dromostanolone propionate, megestrol acetate, nandrolone (decanoate, phenpropionate), dexamethasone

agoniste ili antagoniste gonadotropin-oslobađajućeg hormona, na primer, abareliks, goserelin acetat, histrelin acetat, leuprolid acetat gonadotropin-releasing hormone agonists or antagonists, eg abarelix, goserelin acetate, histrelin acetate, leuprolide acetate

talidomid, lenalidomid thalidomide, lenalidomide

Merkaptopurin, mitotan, pamidronat, pegademazu, pegazpargazu, rasburikazu Mercaptopurine, mitotane, pamidronate, pegademazu, pegazpargasu, rasburikazu

mimetike BH3, na primer, ABT-737 BH3 mimetics, for example, ABT-737

inhibitore MEK, na primer, PD98059, AZD6244, CI-1040 MEK inhibitors, eg PD98059, AZD6244, CI-1040

analoge faktora stimulacije kolonije, na primer, filgrastim, pegfilgrastim, sargramostim; eritropoetin ili njegove analoge (npr. darbepoetin alfa); interleukin 11; oprelvekin; zoledronat, zolendronsku kiselinu; fentanil; bisfosfonat; palifermin colony stimulating factor analogs, for example, filgrastim, pegfilgrastim, sargramostim; erythropoietin or its analogues (eg darbepoetin alfa); interleukin 11; oprelvekin; zoledronate, zolendronic acid; fentanyl; bisphosphonate; palifermin

steroidni inhibitor citohrom P450 17alfa-hidroksilaza-17,20-lijaze (CYP17), npr. abirateron, abirateron acetat steroid inhibitor of cytochrome P450 17alpha-hydroxylase-17,20-lyase (CYP17), e.g. abiraterone, abiraterone acetate

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• inhibitore glikolize kao što je 2-dezoksiglukoza • glycolysis inhibitors such as 2-deoxyglucose

• inhibitore mTOR kao što su rapamicini i rapalozi, i inhibitore mTOR kinaze • mTOR inhibitors such as rapamycins and rapalogs, and mTOR kinase inhibitors

• inhibitore PI3K i dvojne inhibitore mTOR/PI3K • PI3K inhibitors and dual mTOR/PI3K inhibitors

• inhibitore autofagije, kao što su hlorohin i hidroksi-hlorohin • autophagy inhibitors, such as chloroquine and hydroxychloroquine

• antitela koja ponovo aktiviraju imunski odgovor na tumore, na primer, nivolumab (anti-PD-1), lambrolizumab (anti-PD-1), ipilimumab (anti-CTLA4) i MPDL3280A (anti-PD-L1). • antibodies that reactivate the immune response to tumors, for example, nivolumab (anti-PD-1), lambrolizumab (anti-PD-1), ipilimumab (anti-CTLA4) and MPDL3280A (anti-PD-L1).

[0339] Predmetni pronalazak se dalje odnosi na proizvod koji sadrži kao prvi aktivni sastojak jedinjenje iz pronalaska i kao dodatni aktivni sastojak jedan ili više antikancerskih agensa, kao kombinovani preparat za istovremenu, zasebnu ili rednu upotrebu u lečenju pacijenata koji boluju od kancera. [0339] The present invention further relates to a product containing as the first active ingredient the compound of the invention and as an additional active ingredient one or more anticancer agents, as a combined preparation for simultaneous, separate or regular use in the treatment of patients suffering from cancer.

[0340] Jedan ili više drugih medicinskih agensa i jedinjenje iz predmetnog pronalaska može da se primenjuje istovremeno (npr. u zasebnim ili jedinstvenim kompozicijama) ili sekvencijalno bilo kojim redosledom. U potonjem slučaju, dva ili više jedinjenja će se primenjivati u periodu i u količini i na način koji su dovoljni da se obezbedi postizanje pogodnog ili sinergijskog dejstva. Biće jasno da će poželjni postupak i redosled primene i odgovarajuće dozne količine i režimi za svaku komponentu kombinacije zavisiti od konkretnog drugog medicinskog agensa i jedinjenja iz predmetnog pronalaska koji se primenjuju, njihovog načina primene, konkretnog tumora koji se leči i konkretnog domaćina koji se leči. Optimalni postupak i redosled primene i dozne količine i režim stručnjaci jednostavno mogu da odrede koristeći uobičajene postupke i imajući u vidu informacije koje su ovde date. [0340] One or more other medicinal agents and a compound of the present invention may be administered simultaneously (eg, in separate or unique compositions) or sequentially in any order. In the latter case, two or more compounds will be administered for a period and in an amount and in a manner sufficient to ensure the achievement of a favorable or synergistic effect. It will be appreciated that the preferred method and sequence of administration and the appropriate dosage amounts and regimens for each component of the combination will depend on the particular second medicinal agent and compound of the present invention being administered, their route of administration, the particular tumor being treated and the particular host being treated. The optimal procedure and sequence of administration and dosage amount and regimen can easily be determined by those skilled in the art using conventional procedures and bearing in mind the information provided herein.

[0341] Stručnjak može da odredi maseni odnos jedinjenja iz predmetnog pronalaska i jednog ili više drugih antikancerskih agensa kada se daju kao kombinacija. Navedeni odnos i tačna doza i učestalost primene zavise od konkretnog jedinjenja iz pronalaska i drugih antikancerskih agensa koji se koriste, konkretnog stanja koje se leči, težine stanja koje se leči, starosti, težine, pola, ishrane, vremena primene i opšteg fizičkog stanja konkretnog pacijenta, načina primene, [0341] One skilled in the art can determine the weight ratio of a compound of the present invention and one or more other anticancer agents when administered as a combination. The stated ratio and the exact dose and frequency of administration depend on the particular compound of the invention and other anticancer agents used, the particular condition being treated, the severity of the condition being treated, the age, weight, sex, diet, time of administration and general physical condition of the particular patient, the method of administration,

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kao i od drugih lekova koje pojedinac možda uzima, kao što je dobro poznato stručnjacima. Nadalje, jasno je da delotvorna dnevna količina može da se smanji ili poveća u zavisnosti od odgovora lečenog ispitanika i/ili u zavisnosti od procene lekara koji prepisuje jedinjenja iz ovog pronalaska. Konkretni maseni odnos za predmetno jedinjenje formule (I) i drugi antikancerski agens može biti u rasponu od 1/10 do 10/1, konkretnije od 1/5 do 5/1, još konkretnije od 1/3 do 3/1. as well as from other medications that the individual may be taking, as is well known to those skilled in the art. Furthermore, it is clear that the effective daily amount may be decreased or increased depending on the response of the treated subject and/or depending on the judgment of the physician prescribing the compounds of the present invention. The specific mass ratio for the subject compound of formula (I) and the other anticancer agent may be in the range of 1/10 to 10/1, more specifically 1/5 to 5/1, even more specifically 1/3 to 3/1.

[0342] Koordinaciono jedinjenje platine se pogodno primenjuje u dozi od 1 do 500 mg po metru kvadratnom (mg/m<2>) telesne površine, na primer, 50 do 400 mg/m<2>, konkretno za cisplatin u dozi od oko 75 mg/m<2>i za karboplatin oko 300 mg/m<2>po ciklusu lečenja. [0342] The platinum coordination compound is conveniently administered at a dose of 1 to 500 mg per square meter (mg/m<2>) of body surface, for example, 50 to 400 mg/m<2>, specifically for cisplatin at a dose of about 75 mg/m<2> and for carboplatin about 300 mg/m<2> per treatment cycle.

[0343] Jedinjenje taksana se pogodno primenjuje u dozi od 50 do 400 mg po metru kvadratnom (mg/m<2>) telesne površine, na primer, 75 do 250 mg/m<2>, konkretno za paklitaksel u dozi od oko 175 do 250 mg/m<2>i za docetaksel oko 75 do 150 mg/m<2>po ciklusu lečenja. [0343] The taxane compound is conveniently administered at a dose of 50 to 400 mg per square meter (mg/m<2>) of body surface, for example, 75 to 250 mg/m<2>, specifically for paclitaxel at a dose of about 175 to 250 mg/m<2> and for docetaxel about 75 to 150 mg/m<2> per treatment cycle.

[0344] Jedinjenje kamptotecina se pogodno primenjuje u dozi od 0,1 do 400 mg po metru kvadratnom (mg/m<2>) telesne površine, na primer, 1 do 300 mg/m<2>, konkretno za irinotekan u dozi od oko 100 do 350 mg/m<2>i za topotekan oko 1 do 2 mg/m<2>po ciklusu lečenja. [0344] The camptothecin compound is conveniently administered at a dose of 0.1 to 400 mg per square meter (mg/m<2>) of body surface, for example, 1 to 300 mg/m<2>, specifically for irinotecan at a dose of about 100 to 350 mg/m<2> and for topotecan about 1 to 2 mg/m<2> per treatment cycle.

[0345] Antitumorski derivat podofilotoksina se pogodno primenjuje u dozi od 30 do 300 mg po metru kvadratnom (mg/m<2>) telesne površine, na primer, 50 do 250 mg/m<2>, konkretno za etopozid u dozi od oko 35 do 100 mg/m<2>i za tenipozid oko 50 do 250 mg/m<2>po ciklusu lečenja. [0345] The antitumor derivative of podophyllotoxin is conveniently administered in a dose of 30 to 300 mg per square meter (mg/m<2>) of body surface, for example, 50 to 250 mg/m<2>, specifically for etoposide in a dose of about 35 to 100 mg/m<2> and for teniposide about 50 to 250 mg/m<2> per treatment cycle.

[0346] Antitumorski vinka alkaloid se pogodno primenjuje u dozi od 2 do 30 mg po metru kvadratnom (mg/m<2>) telesne površine, konkretno za vinblastin u dozi od oko 3 do 12 mg/m<2>, za vinkristin u dozi od oko 1 do 2 mg/m<2>, a za vinorelbin u dozi od oko 10 do 30 mg/m<2>po ciklusu lečenja. [0346] Antitumor vinca alkaloid is conveniently administered in a dose of 2 to 30 mg per square meter (mg/m<2>) of body surface, specifically for vinblastine in a dose of about 3 to 12 mg/m<2>, for vincristine in a dose of about 1 to 2 mg/m<2>, and for vinorelbine in a dose of about 10 to 30 mg/m<2> per treatment cycle.

[0347] Antitumorski derivat nukleozida se pogodno primenjuje u dozi od 200 do 2500 mg po metru kvadratnom (mg/m<2>) telesne površine, na primer, 700 do 1500 mg/m<2>, konkretno za 5-FU u dozi od 200 do 500 mg/m<2>, za gemcitabin u dozi od oko 800 do 1200 mg/m<2>i za kapecitabin oko 1000 do 2500 mg/m<2>po ciklusu lečenja. [0347] The antitumor nucleoside derivative is conveniently administered at a dose of 200 to 2500 mg per square meter (mg/m<2>) of body surface, for example, 700 to 1500 mg/m<2>, specifically for 5-FU at a dose of 200 to 500 mg/m<2>, for gemcitabine at a dose of about 800 to 1200 mg/m<2> and for capecitabine about 1000 to 2500 mg/m<2>per treatment cycle.

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[0348] Alkilujući agensi, kao što su azotni iperit i nitrozourea, pogodno se primenjuju u dozi od 100 do 500 mg po metru kvadratnom (mg/m<2>) telesne površine, na primer, 120 do 200 mg/m<2>, konkretno za ciklofosfamid u dozi od oko 100 do 500 mg/m<2>, za hlorambucil u dozi od oko 0,1 do 0,2 mg/kg, za karmustin u dozi od oko 150 do 200 mg/m<2>, a za lomustin u dozi od oko 100 do 150 mg/m<2>po ciklusu lečenja. [0348] Alkylating agents, such as nitrogen mustard and nitrosourea, are conveniently administered at a dose of 100 to 500 mg per square meter (mg/m<2>) of body surface, for example, 120 to 200 mg/m<2>, specifically for cyclophosphamide at a dose of about 100 to 500 mg/m<2>, for chlorambucil at a dose of about 0.1 to 0.2 mg/kg, for carmustine in a dose of about 150 to 200 mg/m<2>, and for lomustine in a dose of about 100 to 150 mg/m<2> per treatment cycle.

[0349] Antitumorski derivat antraciklina se pogodno primenjuje u dozi od 10 do 75 mg po metru kvadratnom (mg/m<2>) telesne površine, na primer, 15 do 60 mg/m<2>, konkretno za doksorubicin u dozi od oko 40 do 75 mg/m<2>, za daunorubicin u dozi od oko 25 do 45 mg/m<2>, a za idarubicin u dozi od oko 10 do 15 mg/m<2>po ciklusu lečenja. [0349] The antitumor anthracycline derivative is conveniently administered in a dose of 10 to 75 mg per square meter (mg/m<2>) of body surface, for example, 15 to 60 mg/m<2>, specifically for doxorubicin in a dose of about 40 to 75 mg/m<2>, for daunorubicin in a dose of about 25 to 45 mg/m<2>, and for idarubicin in doses of about 10 to 15 mg/m<2> per treatment cycle.

[0350] Antiestrogeni agens se pogodno primenjuje u dozi od oko 1 do 100 mg dnevno, u zavisnosti od konkretnog agensa i stanja koje se leči. Tamoksifen se pogodno primenjuje oralno u dozi od 5 do 50 mg, poželjno 10 do 20 mg dva puta dnevno, uz dovoljno trajanje terapije za postizanje i održavanje terapeutskog dejstva. Toremifen se pogodno primenjuje oralno u dozi od oko 60 mg jednom dnevno, uz dovoljno trajanje terapije za postizanje i održavanje terapeutskog dejstva. Anastrozol se pogodno primenjuje oralno u dozi od oko 1 mg jednom dnevno. Droloksifen se pogodno primenjuje oralno u dozi od oko 20-100 mg jednom dnevno. Raloksifen se pogodno primenjuje oralno u dozi od oko 60 mg jednom dnevno. Eksemestan se pogodno primenjuje oralno u dozi od oko 25 mg jednom dnevno. [0350] The antiestrogenic agent is conveniently administered in a dose of about 1 to 100 mg per day, depending on the specific agent and the condition being treated. Tamoxifen is conveniently administered orally in a dose of 5 to 50 mg, preferably 10 to 20 mg twice a day, with a sufficient duration of therapy to achieve and maintain the therapeutic effect. Toremifene is conveniently administered orally in a dose of about 60 mg once a day, with a sufficient duration of therapy to achieve and maintain a therapeutic effect. Anastrozole is conveniently administered orally at a dose of about 1 mg once daily. Droloxifene is conveniently administered orally at a dose of about 20-100 mg once daily. Raloxifene is conveniently administered orally at a dose of about 60 mg once daily. Exemestane is conveniently administered orally at a dose of about 25 mg once daily.

[0351] Antitela se pogodno primenjuju u dozi od oko 1 do 5 mg po metru kvadratnom (mg/m<2>) telesne površine, ili kao što je poznato u struci, u slučaju da je drugačije. Trastuzumab se pogodno primenjuje u dozi od 1 do 5 mg po metru kvadratnom (mg/m<2>) telesne površine, naročito 2 do 4 mg/m<2>po ciklusu lečenja. [0351] Antibodies are conveniently administered at a dose of about 1 to 5 mg per square meter (mg/m<2>) of body surface, or as known in the art, if otherwise. Trastuzumab is conveniently administered at a dose of 1 to 5 mg per square meter (mg/m<2>) of body surface, particularly 2 to 4 mg/m<2> per treatment cycle.

[0352] Ove doze mogu da se primene, na primer, jednom, dva puta ili više po ciklusu lečenja, koji može da se ponavlja, na primer, na svakih 7, 14, 21 ili 28 dana. [0352] These doses may be administered, for example, once, twice or more per treatment cycle, which may be repeated, for example, every 7, 14, 21 or 28 days.

[0353] Sledeći primeri ilustruju predmetni pronalazak. U slučaju da nema konkretne stereohemije naznačene za stereocentar jedinjenja, to znači da je dobijena smeša R i S enantiomera. U slučaju da je u strukturi prisutno više od 1 stereocentra, svaki stereocentar za koji nije naznačena konkretna stereohemija dobijen je kao smeša R i S. [0353] The following examples illustrate the present invention. In case there is no specific stereochemistry indicated for the stereocenter of the compound, it means that a mixture of R and S enantiomers is obtained. In case more than 1 stereocenter is present in the structure, each stereocenter for which the specific stereochemistry is not indicated is obtained as a mixture of R and S.

1 1

[0354] Stručnjaku će biti jasno da su nakon prečišćavanja na koloni željene frakcije obično sakupljene, i rastvarač je uparen radi dobijanja željenog jedinjenja ili intermedijera. [0354] One skilled in the art will appreciate that after column purification, the desired fractions are usually collected, and the solvent is evaporated to provide the desired compound or intermediate.

Primeri Examples

[0355] Nadalje, termin „rt“, „r.t.“ ili „RT“ označava sobnu temperaturu; „Me“ označava metil; „MeOH“ označava metanol; „Et“ označava etil; „EtOH“ označava etanol; „NaH“ označava natrijum hidrid; „DEAD“ označava dietil azodikarboksilat; „HMPT“ označava heksametil fosfor triamid; „Boc2O“ označava terc-butoksikarbonil anhidrid; „Bu'ONO“ označava tercbutil nitrit; „TosOH“ označava 4-metil benzensulfonsku kiselinu; „TosCl“ označava 4-metil benzensulfonil hlorid (takođe p-toluensulfonil hlorid); „CMBP“ označava cijanometilen tributilfosforan; „DBAD“ označava di-terc-butil azodikarboksilat; „LAH“ označava litijum aluminijum hidrid; „NaBH(AcO)3“ ili „NaBH(OAc)3“ označava natrijum triacetoksi borhidrid; „EtOAc“ označava etil acetat; „TEA“ ili „Et3N“ označava trietilamin; „DCM“ označava dihlormetan; „q.s.“ znači dovoljna količina; „Int.“ označava intermedijer; „MeCN“ ili „ACN“ označava acetonitril; „DMF“ označava N,N-dimetil formamid; „DMA“ označava N,N-dimetilacetamid; „DMF-DMA“ označava N,N-dimetilformamid dimetil acetal; „Pd(dppf)Cl2“ označava [1,1'-bis(difenilfosfino)ferocen]dihlorpaladijum(II); „THF“ označava tetrahidrofuran; „C34H28FeP2.Cl2Pd“ označava [1,1'-bis(difenilfosfino)ferocen] dihlorpaladijum(ii); „i-PrOH“ ili „iPrOH“ označava 2-propanol; „LC“ označava tečnu hromatografiju; „LCMS“ označava tečnu hromatografiju/masenu spektrometriju; „HPLC“ označava tečnu hromatografiju visokih performansi; „int.“ označava intermedijer; „prep-HPLC“ označava preparativnu tečnu hromatografiju visokih performansi; „m-CPBA“ označava meta-hlor peroksibenzojevu kiselinu; „TFA“ označava trifluorsirćetnu kiselinu; „m.p.“ označava tačku topljenja; „RP“ označava reversnu fazu; „min“ označava minut(e); „h“ označava sat(e); „PE“ označava petrol etar; „v/v“ znači zapremina kroz zapreminu; „Celite®“ označava dijatomejsku zemlju; „DMSO“ označava dimetil sulfoksid; „SFC“ označava superkritičnu tečnu hromatografiju; „DIPE“ označava diizopropil etar; „dppf“ ili „DPPF“ označava 1,1'-bis(difenilfosfino)ferocen; „DIPEA“ ili „DIEA“ označava N,N-diizopropiletilamin; „PPh3“ označava trifenilfosfin; „Et2O“ označava dietil etar; „Pd/C“ označava paladijum na ugljeniku; „Pt/C“ označava platinu na ugljeniku; „Pd(OH)2/C“ označava paladijum hidroksid na ugljeniku; „CPME“ označava ciklopentil metil etar; „Pd2(dba)3“ označava tris(dibenzilidenaceton)dipaladijum; „DIAD“ označava diizopropil azodikarboksilat; „TMSCF3“ označava trimetil(trifluormetil)silan; „TBAF“ označava [0355] Furthermore, the term "rt", "r.t." or "RT" means room temperature; "Me" means methyl; "MeOH" means methanol; "Et" means ethyl; "EtOH" means ethanol; "NaH" means sodium hydride; "DEAD" means diethyl azodicarboxylate; "HMPT" means hexamethyl phosphorus triamide; "Boc2O" means tert-butoxycarbonyl anhydride; "Bu'ONO" means tert-butyl nitrite; "TosOH" means 4-methyl benzenesulfonic acid; "TosCl" means 4-methyl benzenesulfonyl chloride (also p-toluenesulfonyl chloride); "CMBP" means cyanomethylene tributylphosphorane; "DBAD" means di-tert-butyl azodicarboxylate; "LAH" means lithium aluminum hydride; "NaBH(AcO)3" or "NaBH(OAc)3" means sodium triacetoxy borohydride; "EtOAc" means ethyl acetate; "TEA" or "Et3N" means triethylamine; "DCM" means dichloromethane; "q.s." means sufficient quantity; "Int." means intermediate; "MeCN" or "ACN" means acetonitrile; "DMF" means N,N-dimethyl formamide; "DMA" means N,N-dimethylacetamide; "DMF-DMA" means N,N-dimethylformamide dimethyl acetal; "Pd(dppf)Cl2" means [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II); "THF" means tetrahydrofuran; "C34H28FeP2.Cl2Pd" means [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium(ii); "i-PrOH" or "iPrOH" means 2-propanol; "LC" stands for liquid chromatography; "LCMS" means liquid chromatography/mass spectrometry; "HPLC" means High Performance Liquid Chromatography; "int." means intermediate; "prep-HPLC" means preparative high-performance liquid chromatography; "m-CPBA" means meta-chloro peroxybenzoic acid; "TFA" means trifluoroacetic acid; "m.p." indicates the melting point; "RP" means reverse phase; "min" means minute(s); "h" stands for hour(s); "PE" means petroleum ether; "v/v" means volume by volume; "Celite®" means diatomaceous earth; "DMSO" means dimethyl sulfoxide; "SFC" means supercritical liquid chromatography; "DIPE" means diisopropyl ether; "dppf" or "DPPF" means 1,1'-bis(diphenylphosphino)ferrocene; "DIPEA" or "DIEA" means N,N-diisopropylethylamine; "PPh3" means triphenylphosphine; "Et2O" means diethyl ether; "Pd/C" means palladium on carbon; "Pt/C" means platinum on carbon; "Pd(OH)2/C" means palladium hydroxide on carbon; "CPME" means cyclopentyl methyl ether; "Pd2(dba)3" means tris(dibenzylideneacetone)dipalladium; "DIAD" means diisopropyl azodicarboxylate; "TMSCF3" means trimethyl(trifluoromethyl)silane; "TBAF" stands for

1 1 1 1

tetrabutil amonijum fluorid; „psi“ označava funtu sile po kvadratnom inču; „Et4NCl“ označava tetraetil amonijum hlorid; „ekv.“ označava ekvivalent(e); „Pd(OAc)2“ označava paladijum(II) acetat; „AcOH“ označava sirćetnu kiselinu; „DMAP“ označava 4-(dimetilamino)piridin; „t-BuOK“, „<t>BuOK“ ili „KOtBu“ označava kalijum terc-butoksid; „Des-Martinov perjodinan“ označava 1,1,1-triacetoksi-1,1-dihidro-1,2-benziodoksol-3(1H)-on; „TBDMSCl“ označava terc-butil dimetilsilil hlorid; „PPh3-polimer“ ili „PPh3-pol“ označava trifenilfosfinsku polimernu vezu; „Ph3PCH3Br“ označava metil trifenil fosfonijum bromid; „Bn“ označava benzil; „Bz“ označava benzoil; „p-TSA“ označava 4-metilbenzensulfonsku kiselinu; „BF3.Et2O“ označava kompleks bor trifluorid-etil etar; „9-BBN“ označava 9-borabiciklo[3.3.1]nonan; „Pd-118“ označava dihlor[1,1'-bis(di-tercbutilfosfino)ferocen]paladijum(II); i „TLC“ označava tankoslojnu hromatografiju; „prep-TLC“ označava preparativnu TLC; tetrabutyl ammonium fluoride; "psi" means pounds of force per square inch; "Et4NCl" means tetraethyl ammonium chloride; "eq." indicates equivalent(s); "Pd(OAc)2" means palladium(II) acetate; "AcOH" means acetic acid; "DMAP" means 4-(dimethylamino)pyridine; "t-BuOK", "<t>BuOK" or "KOtBu" means potassium tert-butoxide; "Des-Martin periodinan" means 1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one; "TBDMSCl" means tert-butyl dimethylsilyl chloride; "PPh3-polymer" or "PPh3-pol" means a triphenylphosphine polymer bond; "Ph3PCH3Br" means methyl triphenyl phosphonium bromide; "Bn" means benzyl; "Bz" means benzoyl; "p-TSA" means 4-methylbenzenesulfonic acid; "BF3.Et2O" means boron trifluoride-ethyl ether complex; "9-BBN" means 9-borabicyclo[3.3.1]nonane; "Pd-118" means dichloro[1,1'-bis(di-tertbutylphosphino)ferrocene]palladium(II); and "TLC" means thin layer chromatography; "prep-TLC" means preparative TLC;

„p-MeC6H4SO3H.H2O“ označava hidrat para toluensulfonske kiseline; „PMB“ označava para metoksibenzil; „KOAc“ označava kalijum acetat; „PTSA“ para-toluensulfonsku kiselinu; „MTBE“ označava metil terc-butil etar; „Rh(acac)(eth)2“ označava acetilacetonatobis(etilen)rodijum(I); „(S)-MonoPhos“ označava (S)-N,N-dimetildinafto[2,1-D:1',2'-F][1,3,2]dioksafosfepin-4-amin; „Tf2O“ označava anhidrid trifluormetansulfonske kiseline; „Mel“ označava metil jodid; „Me2NH“ označava dimetilamin; „Me2NH.HCl“ označava dimetilamin hlorovodoničnu kiselinu; „Me4NCl“ označava tetrametil amonijum hlorid; „MeONa“ označava natrijum metoksid; „Ts“ označava tozil; „MsCl“ označava mezil hlorid; „DIBAH“ označava diizobutil aluminijum hidrid; „TBDMS“ označava terc-butil dimetilsilil; „Pd(dppf)Cl2.CH2Cl2“ označava [1,1'-bis(difenilfosfino)ferocen]dihlorpaladijum(II), kompleks sa dihlormetanom; „PPA“ označava polifosfornu kiselinu; „NH2Bn“ označava benzilamin; „Pd(PPh3)2Cl2“ označava dihlorbis(trifenilfosfin)paladijum(II). "p-MeC6H4SO3H.H2O" means toluenesulfonic acid vapor hydrate; "PMB" means para methoxybenzyl; "KOAc" means potassium acetate; "PTSA" para-toluenesulfonic acid; "MTBE" means methyl tert-butyl ether; "Rh(acac)(eth)2" means acetylacetonatobis(ethylene)rhodium(I); "(S)-MonoPhos" means (S)-N,N-dimethyldinaphtho[2,1-D:1',2'-F][1,3,2]dioxaphosphepin-4-amine; "Tf2O" means trifluoromethanesulfonic acid anhydride; "Mel" means methyl iodide; "Me2NH" means dimethylamine; "Me2NH.HCl" means dimethylamine hydrochloric acid; "Me4NCl" means tetramethyl ammonium chloride; "MeONa" means sodium methoxide; "Ts" stands for tosyl; "MsCl" means mesyl chloride; "DIBAH" means diisobutyl aluminum hydride; "TBDMS" means tert-butyl dimethylsilyl; "Pd(dppf)Cl2.CH2Cl2" means [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane; "PPA" means polyphosphoric acid; "NH2Bn" means benzylamine; "Pd(PPh3)2Cl2" means dichlorobis(triphenylphosphine)palladium(II).

[0356] Intermedijeri koji sadrže dvostruku vezu sa supstituentima koji mogu biti u E ili Z konfiguraciji prikazani su u jednoj konkretnoj konfiguraciji u eksperimentalnom delu u nastavku. Međutim, osim ako nije izričito naznačeno putem (E) ili (Z), nije poznato da li su ovi intermedijeri dobijeni u E ili Z konfiguraciji ili kao smeša obe konfiguracije. Na primer, intermedijeri 24-26, 29-31, 72-76 i intermedijeri 79-88 mogu biti u E ili Z konfiguraciji, ili mogu biti njihove smeše. [0356] Intermediates containing a double bond with substituents that can be in the E or Z configuration are shown in one particular configuration in the experimental section below. However, unless specifically indicated by (E) or (Z), it is not known whether these intermediates are obtained in the E or Z configuration or as a mixture of both configurations. For example, intermediates 24-26, 29-31, 72-76 and intermediates 79-88 may be in the E or Z configuration, or may be mixtures thereof.

1 2 1 2

[0357] Na primer, intermedijeri 44, 97-100, 136-138, 150 i jedinjenja 55, 57, 57a i 61 dobijeni su u E konfiguraciji, i izričito su označeni kao takvi (E) u eksperimentalnom delu u nastavku. [0357] For example, intermediates 44, 97-100, 136-138, 150 and compounds 55, 57, 57a, and 61 were obtained in the E configuration, and are explicitly designated as such (E) in the experimental section below.

[0358] Za intermedijere koji su korišćeni u sledećem reakcionom koraku kao sirova supstanca ili kao delimično prečišćeni intermedijer, procenjene molske količine (u nekim slučajevima označene sa ≈) naznačene su u reakcionim protokolima koji su opisani u nastavku, ili su alternativno naznačene teorijske molske količine. [0358] For intermediates that were used in the next reaction step as a crude substance or as a partially purified intermediate, estimated molar amounts (in some cases denoted by ≈) are indicated in the reaction protocols described below, or alternatively theoretical molar amounts are indicated.

A. Priprema intermedijera A. Preparation of intermediates

[0359] Primer A1 [0359] Example A1

Priprema intermedijera 1 Preparation of intermediate 1

[0360] [0360]

[0361] U smešu 6-hlor-7-deazapurinbeta-d-ribozida (25,0 g, 87,5 mmol) u acetonu (330 ml) dodat je 2,2-dimetoksipropan (18,2 g, 175 mmol) i 4-metilbenzensulfonska kiselina (TosOH) (1,51 g, 8,75 mmol) u jednoj porciji na 25°C u atmosferi N2. Smeša je mešana na 60°C tokom 2 sata. Smeša je ohlađena na 25°C. Reakcija je deaktivirana sporim dodavanjem zasićenog NaHCO3(100 ml), a zatim je ekstrahovana etil acetatom (125 ml x 5). Kombinovana organska faza je isprana zasićenim vodenim rastvorom soli (120 ml), osušena pomoću anhidrovanog MgSO4, filtrirana i koncentrovana pod vakuumom. Ostatak je prečišćen hromatografijom na silika gelu (elucioni gradijent: DCM/etil acetat od 1:0 do 2:1) radi dobijanja sirovog intermedijera 1 (38,0 g) kao svetložute gume. [0361] To a mixture of 6-chloro-7-deazapurinebeta-d-riboside (25.0 g, 87.5 mmol) in acetone (330 ml) was added 2,2-dimethoxypropane (18.2 g, 175 mmol) and 4-methylbenzenesulfonic acid (TosOH) (1.51 g, 8.75 mmol) in one portion at 25°C under N2 atmosphere. The mixture was stirred at 60°C for 2 hours. The mixture was cooled to 25°C. The reaction was quenched by slow addition of saturated NaHCO3 (100 mL) and then extracted with ethyl acetate (125 mL x 5). The combined organic phase was washed with brine (120 mL), dried over anhydrous MgSO 4 , filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (elution gradient: DCM/ethyl acetate from 1:0 to 2:1) to give crude intermediate 1 (38.0 g) as a pale yellow gum.

1 1

Primer A2 Example A2

Priprema intermedijera 3 Preparation of intermediate 3

[0362] [0362]

[0363] U rastvor 5-O-terc-butil dimetilsilil-2,3-o-izopropiliden-D-ribofuranoze (intermedijer 2) (24,3 g, 79,8 mmol) u CCl4(12,8 ml, 133 mmol) i toluenu (200 ml) u kapima je dodat HMPT na -50°C tokom 30 minuta. Nakon što je smeša mešana na -50°C tokom 2 sata, reakciona smeša je brzo isprana ledeno hladnim zasićenim vodenim rastvorom soli (30 ml), osušena iznad anhidrovanog Na2SO4i smesta je uz snažno mešanje dodata u smešu praškastog KOH (6,5 g, 117 mmol), 2,4-dihlor-7h-pirolopirimidina (10,0 g, 53 mmol), tris(3,6-dioksaheptil)amina (8,27 ml, 26,6 mmol) i toluena (200 ml). Smeša je mešana na sobnoj temperaturi tokom 48 sati. Rastvarač je zatim koncentrovan pod vakuumom. Ostatak je tretiran sa 250 ml rastvora NH4Cl i ekstrahovan je etil acetatom (300 ml x 2). Organski slojevi su kombinovani i osušeni pomoću Na2SO4, filtrirani, i filtrat je koncentrovan pod vakuumom. Ostatak je prečišćen hromatografijom na koloni silika gela (elucioni gradijent: petrol etar/etil acetat od 25:1 do 15:1). Frakcije proizvoda su sakupljene i rastvarač je uparen radi dobijanja željenog intermedijera 3 (6,50 g, sirova supstanca) [0363] To a solution of 5-O-tert-butyl dimethylsilyl-2,3-o-isopropylidene-D-ribofuranose (intermediate 2) (24.3 g, 79.8 mmol) in CCl 4 (12.8 ml, 133 mmol) and toluene (200 ml) was added HMPT dropwise at -50°C over 30 minutes. After the mixture was stirred at -50°C for 2 hours, the reaction mixture was washed rapidly with ice-cold saturated aqueous salt solution (30 mL), dried over anhydrous Na2SO4, and was added with vigorous stirring to a mixture of powdered KOH (6.5 g, 117 mmol), 2,4-dichloro-7h-pyrrolopyrimidine (10.0 g, 53 mmol), tris(3,6-dioxaheptyl)amine (8.27 ml, 26.6 mmol) and toluene (200 ml). The mixture was stirred at room temperature for 48 hours. The solvent was then concentrated under vacuum. The residue was treated with 250 ml of NH4Cl solution and extracted with ethyl acetate (300 ml x 2). The organic layers were combined and dried over Na 2 SO 4 , filtered, and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (elution gradient: petroleum ether/ethyl acetate from 25:1 to 15:1). The product fractions were collected and the solvent was evaporated to give the desired intermediate 3 (6.50 g, crude substance)

[0364] Sledeći intermedijeri su pripremljeni reakcionim protokolom koji je analogan protokolu korišćenom za pripremu intermedijera 3 koristeći odgovarajuće polazne supstance (Tabela 1). [0364] The following intermediates were prepared by a reaction protocol that is analogous to the protocol used for the preparation of intermediate 3 using the appropriate starting substances (Table 1).

Tabela 1: Table 1:

1 4 1 4

1 1

Primer A3 Example A3

Priprema intermedijera 6 Preparation of intermediate 6

[0365] [0365]

[0366] Intermedijer 3 (7,00 g, 14,8 mmol) rastvoren je u smeši rastvarača sirćetne kiseline, vode i THF u odnosu od 13:7:3 (100 ml). Reakciona smeša je mešana na sobnoj temperaturi tokom 12 sati. Rastvarač je uklonjen pod sniženim pritiskom na 60°C, što daje 6,8 g sirovog intermedijera 6 zajedno sa nusproizvodom. U rastvor prethodnog sirovog proizvoda u acetonu (50 ml) dodat je 2,2-dimetoksipropan (5 ml, 42 mmol) i 4-metil benzensulfonska kiselina monohidrat (13 mg, 0,07 mmol) na sobnoj temperaturi u atmosferi N2. Smeša je mešana na 60°C tokom 2 sata. Rastvarač je uklonjen pod sniženim pritiskom na temperaturi ispod 30°C. Ostatak je prečišćen hromatografijom na koloni (elucioni gradijent: EtOAc/petrol etar od 1/10 do 1/3) na silika gelu radi dobijanja željenog intermedijera 6 (3,02 g, prinos 34%). [0366] Intermediate 3 (7.00 g, 14.8 mmol) was dissolved in a solvent mixture of acetic acid, water and THF in the ratio of 13:7:3 (100 ml). The reaction mixture was stirred at room temperature for 12 hours. The solvent was removed under reduced pressure at 60 °C, yielding 6.8 g of crude intermediate 6 along with a by-product. To a solution of the previous crude product in acetone (50 mL) was added 2,2-dimethoxypropane (5 mL, 42 mmol) and 4-methyl benzenesulfonic acid monohydrate (13 mg, 0.07 mmol) at room temperature under N2 atmosphere. The mixture was stirred at 60°C for 2 hours. The solvent was removed under reduced pressure at a temperature below 30°C. The residue was purified by column chromatography (elution gradient: EtOAc/petroleum ether from 1/10 to 1/3) on silica gel to give the desired intermediate 6 (3.02 g, 34% yield).

Primer A4 Example A4

Priprema intermedijera 7 Preparation of intermediate 7

1 1

[0368] U rastvor intermedijera 4 (9,50 g, 20,9 mmol) u THF-u (82 ml) dodat je 1 M rastvor TBAF u THF-u (41,8 ml, 41,8 mmol) na sobnoj temperaturi. Reakciona smeša je mešana na sobnoj temperaturi tokom 3 sata. Smeša je uparena do suva. Ostatak je prenet u vodu i ekstrahovan pomoću DCM (150 ml x 2). Organski slojevi su osušeni (Na2SO4), filtrirani, i filtrat je koncentrovan pod vakuumom. Ostatak je prečišćen hromatografijom na koloni silika gela (elucioni gradijent: petrol etar/etil acetat od 10/1 do 4/1) radi dobijanja željenog intermedijera 7 (3,68 g, prinos 88%) [0368] To a solution of intermediate 4 (9.50 g, 20.9 mmol) in THF (82 ml) was added a 1 M solution of TBAF in THF (41.8 ml, 41.8 mmol) at room temperature. The reaction mixture was stirred at room temperature for 3 hours. The mixture was evaporated to dryness. The residue was taken up in water and extracted with DCM (150 ml x 2). The organic layers were dried (Na 2 SO 4 ), filtered, and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (elution gradient: petroleum ether/ethyl acetate from 10/1 to 4/1) to give the desired intermediate 7 (3.68 g, 88% yield)

[0369] Sledeći intermedijer je pripremljen reakcionim protokolom koji je analogan protokolu korišćenom za pripremu intermedijera 7 koristeći odgovarajuće polazne supstance (Tabela 2). [0369] The following intermediate was prepared by a reaction protocol analogous to the protocol used for the preparation of intermediate 7 using the appropriate starting substances (Table 2).

Tabela 2: Table 2:

1 1

Primer A5 Example A5

Priprema intermedijera 10 Preparation of intermediates 10

[0370] [0370]

Korak a) Step a)

[0371] [0371]

1 1

U smešu 4,6-dihlor-5-(2,2-dietoksietil)pirimidina (14,0 g, 52,8 mmol) i (1R,2S,3R,5R)-3-amino-5-(hidroksimetil)ciklopentan-1,2-diol hidrohlorida (10,7 g, 58,1 mmol) u smeši propan-2-ol/H2O (208 ml, 7:1), u jednoj porciji je dodat Et3N (13,4 g, 132 mmol) na 25°C u atmosferi N2. Smeša je mešana na 90°C tokom 23 sata. Smeša je ohlađena na 50°C i polako je dodata 4 M HCl (24 ml, 106 mmol). Ostatak je zatim mešan na 50°C tokom 2 sata. Reakciona smeša je ohlađena na 25°C, i polako je dodat NaHCO3(14 g, 100 mmol). Dodat je etil acetat (230 ml), nakon čega je dodat poluzasićeni rastvor NaHCO3(dovoljna količina). Organska faza je izolovana i vodena faza je ekstrahovana pomoću etil acetata (230 ml x 2). Kombinovana organska faza je osušena pomoću anhidrovanog MgSO4, filtrirana i koncentrovana pod vakuumom radi dobijanja intermedijera 9 kao žute čvrste supstance (17,4 g, kvantitativni prinos za 2 koraka). Sirovi proizvod je neposredno korišćen u datom stanju u sledećem koraku reakcije bez daljeg prečišćavanja. To a mixture of 4,6-dichloro-5-(2,2-diethoxyethyl)pyrimidine (14.0 g, 52.8 mmol) and (1R,2S,3R,5R)-3-amino-5-(hydroxymethyl)cyclopentane-1,2-diol hydrochloride (10.7 g, 58.1 mmol) in a mixture of propan-2-ol/H2O (208 mL, 7:1) was added in one portion. added Et3N (13.4 g, 132 mmol) at 25°C under N2 atmosphere. The mixture was stirred at 90°C for 23 hours. The mixture was cooled to 50°C and 4 M HCl (24 mL, 106 mmol) was slowly added. The residue was then stirred at 50°C for 2 hours. The reaction mixture was cooled to 25°C, and NaHCO3 (14 g, 100 mmol) was slowly added. Ethyl acetate (230 ml) was added, followed by half-saturated NaHCO3 solution (sufficient amount). The organic phase was isolated and the aqueous phase was extracted with ethyl acetate (230 ml x 2). The combined organic phase was dried over anhydrous MgSO 4 , filtered and concentrated in vacuo to afford intermediate 9 as a yellow solid (17.4 g, quantitative yield over 2 steps). The crude product was directly used as is in the next step of the reaction without further purification.

Korak b) Step b)

[0372] [0372]

[0373] U smešu intermedijera 9 (17,4 g, ≈52,7 mmol) u acetonu (250 ml) dodat je 2,2-dimetoksipropan (11,0 g, 105 mmol) i TsOH.H2O (908 mg, 5,27 mmol) u jednoj porciji na 25°C u atmosferi N2. Smeša je mešana na 60°C tokom 2 sata. Smeša je ohlađena na 25°C i rastvor je koncentrovan pod vakuumom, polako deaktiviran pomoću zasićenog NaHCO3(100 ml), a zatim je ekstrahovan etil acetatom (100 ml x 3). Kombinovana organska faza je isprana [0373] To a mixture of intermediate 9 (17.4 g, ≈52.7 mmol) in acetone (250 mL) was added 2,2-dimethoxypropane (11.0 g, 105 mmol) and TsOH.H2O (908 mg, 5.27 mmol) in one portion at 25°C under N2 atmosphere. The mixture was stirred at 60°C for 2 hours. The mixture was cooled to 25°C and the solution was concentrated under vacuum, slowly quenched with saturated NaHCO 3 (100 ml) and then extracted with ethyl acetate (100 ml x 3). The combined organic phase was washed

1 1

zasićenim vodenim rastvorom soli (100 ml), osušena pomoću anhidrovanog MgSO4, filtrirana i koncentrovana pod vakuumom. Ostatak je prečišćen fleš hromatografijom na silika gelu (elucioni gradijent: DCM/etil acetat od 1/0 do 2/1) radi dobijanja intermedijera 10 kao svetložute gume (15,5 g, prinos 89%). brine (100 mL), dried over anhydrous MgSO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (elution gradient: DCM/ethyl acetate from 1/0 to 2/1) to give intermediate 10 as a pale yellow gum (15.5 g, 89% yield).

Primer A6 Example A6

Priprema intermedijera 14 Preparation of intermediates 14

[0374] [0374]

Korak a) Step a)

[0375] [0375]

[0376] U balon osušen u pećnici dodat je 7-brom-4-(metiltio)pirolo[2,1-f][1,2,4]triazin (45,0 g, 184 mmol) i suvi THF (1,20 l) u atmosferi N2. Žuti rastvor je ohlađen na -78°C, i nastala je žuta suspenzija. U reakcionu smešu je u kapima dodat n-BuLi (2,5 M, 79,6 ml) u periodu od 25 minuta na -78°C. Reakciona smeša je mešana na -78°C tokom 1 sata, i nastao je žutosmeđi rastvor. U rastvor je dodat prethodno ohlađeni rastvor intermedijera 10 (84,0 g, 201 mmol) u suvom THF (800 ml) iz drugog balona (-78°C) u atmosferi N2. Dobijeni crvenosmeđi rastvor je mešan na -78°C tokom 1,5 h. 2 šarže su paralelno sprovedene. Reakcija je deaktivirana [0376] To an oven-dried flask was added 7-bromo-4-(methylthio)pyrrolo[2,1-f][1,2,4]triazine (45.0 g, 184 mmol) and dry THF (1.20 L) under N2 atmosphere. The yellow solution was cooled to -78°C, and a yellow suspension was formed. n-BuLi (2.5 M, 79.6 ml) was added dropwise to the reaction mixture over a period of 25 minutes at -78°C. The reaction mixture was stirred at -78°C for 1 hour, and a tan solution was formed. To the solution was added a pre-cooled solution of intermediate 10 (84.0 g, 201 mmol) in dry THF (800 ml) from another flask (-78°C) under N2 atmosphere. The resulting red-brown solution was stirred at -78°C for 1.5 h. 2 batches were run in parallel. The reaction is deactivated

1 1

dodavanjem zasićenog vodenog rastvora NH4Cl (300 ml) na -78°C, i smeša je zatim zagrejana na 10°C. Smeša je ekstrahovana etil acetatom (500 ml x 3). Kombinovani organski slojevi su isprani zasićenim vodenim rastvorom soli, osušeni iznad MgSO4, filtrirani i koncentrovani pod sniženim pritiskom. Ostatak je nanet na silika gel i prečišćen hromatografijom na koloni (SiO2, elucioni gradijent: petrol etar/etil acetat od 10/1 do 3:1) radi dobijanja intermedijera 11 (149 g, prinos 56%) kao narandžaste gume. by adding saturated aqueous NH4Cl (300 mL) at -78°C, and the mixture was then warmed to 10°C. The mixture was extracted with ethyl acetate (500 ml x 3). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was applied to silica gel and purified by column chromatography (SiO2, elution gradient: petroleum ether/ethyl acetate from 10/1 to 3:1) to give intermediate 11 (149 g, yield 56%) as an orange gum.

Korak b) Step b)

[0377] [0377]

[0378] U rastvor intermedijera 11 (74,0 g, 127 mmol) i trietilsilana (59,9 g, 515 mmol) u DCM-u (1,80 l) uz mešanje je ukapan BF3.Et2O (90,9 g, 640 mmol) na -30∼-20°C.2 šarže su paralelno sprovedene. Dobijeni narandžasti rastvor je mešan na temperaturi od -30 do -20°C tokom 4,5 sati. Reakciona smeša je pažljivo sipana u zasićeni vodeni rastvor NaHCO3(2,5 l) uz žustro mešanje (razvijanje gasa). Smeša je mešana tokom 2 sata. Organski sloj je razdvojen, i vodena faza je ekstrahovana pomoću DCM (200 ml x 3). Kombinovani organski slojevi su isprani zasićenim vodenim rastvorom soli (500 ml x 2), osušeni iznad MgSO4, filtrirani i koncentrovani pod sniženim pritiskom. Ostatak je prečišćen hromatografijom na koloni (silika gel, elucioni gradijent: petrol etar:etil acetat: od 12:1 do 8:1), dajući intermedijer 12 kao svetložutu gumu (125,7 g, prinos 83%). [0378] To a solution of intermediate 11 (74.0 g, 127 mmol) and triethylsilane (59.9 g, 515 mmol) in DCM (1.80 L) was added dropwise with stirring BF3.Et2O (90.9 g, 640 mmol) at -30∼-20°C.2 batches were carried out in parallel. The resulting orange solution was stirred at a temperature of -30 to -20°C for 4.5 hours. The reaction mixture was carefully poured into a saturated aqueous solution of NaHCO3 (2.5 l) with vigorous stirring (gas evolution). The mixture was stirred for 2 hours. The organic layer was separated, and the aqueous phase was extracted with DCM (200 ml x 3). The combined organic layers were washed with brine (500 mL x 2), dried over MgSO 4 , filtered and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, elution gradient: petroleum ether:ethyl acetate: from 12:1 to 8:1), giving intermediate 12 as a pale yellow gum (125.7 g, 83% yield).

Korak c) Step c)

[0379] [0379]

1 1 1 1

[0380] 1 M BCl3u CH2Cl2(860 ml, 860 mmol) uz mešanje je u kapima dodat na -78°C u rastvor intermedijera 12 (75,0 g, 132 mmol) u DCM-u (1,20 l) tokom 2,5 sata u atmosferi N2. Smeša je mešana na -78°C tokom 1 sata. Reakciona smeša je polako zagrejana na -40°C. Reakciona smeša je sipana u MeOH (2,5 l, 20°C) uz mešanje. Dobijeni crveni rastvor je mešan tokom 3 sata. U smešu je dodata voda (250 ml) i ostavljena je na 20°C tokom 16 h. Rastvor je u porcijama pažljivo sipan na čvrsti NaHCO3(500 g) uz žustro mešanje (razvijanje gasa, boja smeše je od narandžastocrvene postala žuta). Dobijena suspenzija je filtrirana, i filtrat je koncentrovan pod sniženim pritiskom. Ostatak je prenet u iPrOH/CH2Cl2(1:3, 1 l), zatim je filtriran (radi uklanjanja nekih neorganskih soli) i filtrat je koncentrovan pod sniženim pritiskom. Ostatak je trituriran petrol etrom (500 ml x 3) radi dobijanja sirovog intermedijera 13 (40,2 g, sirova supstanca) kao narandžaste čvrste supstance, koja je korišćena u sledećem koraku reakcije bez daljeg prečišćavanja. [0380] 1 M BCl 3 in CH 2 Cl 2 (860 ml, 860 mmol) was added dropwise at -78°C to a solution of intermediate 12 (75.0 g, 132 mmol) in DCM (1.20 L) over 2.5 hours under N 2 atmosphere. The mixture was stirred at -78°C for 1 hour. The reaction mixture was slowly warmed to -40°C. The reaction mixture was poured into MeOH (2.5 L, 20 °C) with stirring. The resulting red solution was stirred for 3 hours. Water (250 ml) was added to the mixture and it was left at 20°C for 16 h. The solution was carefully poured in portions onto solid NaHCO3 (500 g) with vigorous stirring (evolving gas, the color of the mixture changed from orange-red to yellow). The resulting suspension was filtered, and the filtrate was concentrated under reduced pressure. The residue was taken up in iPrOH/CH 2 Cl 2 (1:3, 1 L), then filtered (to remove some inorganic salts) and the filtrate was concentrated under reduced pressure. The residue was triturated with petroleum ether (500 mL x 3) to afford crude intermediate 13 (40.2 g, crude) as an orange solid, which was used in the next reaction step without further purification.

Korak d) Step d)

[0381] [0381]

[0382] U suspenziju intermedijera 13 (40,2 g, sirova supstanca) i 2,2-dimetoksipropana (34 ml, 277 mmol) u acetonu (600 ml) dodat je TsOH.H2O (5,92 g, 31,10 mmol, 0,23 ekv.) na 25°C (pH = 2). Dobijena smeša je zagrevana na 60°C tokom 2 sata. Nakon što je ohlađena na [0382] To a suspension of intermediate 13 (40.2 g, crude) and 2,2-dimethoxypropane (34 ml, 277 mmol) in acetone (600 ml) was added TsOH.H2O (5.92 g, 31.10 mmol, 0.23 equiv) at 25°C (pH = 2). The resulting mixture was heated at 60°C for 2 hours. After it has cooled down

1 2 1 2

25°C, reakciona smeša je koncentrovana pod sniženim pritiskom. Ostatak je raspodeljen između etil acetata (500 ml) i zasićenog vodenog rastvora NaHCO3(500 ml). Slojevi su razdvojeni, i vodena faza je ekstrahovana etil acetatom (200 ml x 3). Kombinovani organski slojevi su isprani zasićenim vodenim rastvorom soli (100 ml), osušeni iznad MgSO4, filtrirani i koncentrovani pod sniženim pritiskom. Ostatak je prečišćen hromatografijom na koloni (silika gel, elucioni gradijent: CH2Cl2/etil acetat od 10/1 do 6/1). Frakcije koje sadrže željeni intermedijer 14 su kombinovane i koncentrovane pod sniženim pritiskom. Ostatak (28 g, čistoće oko 80%) ponovo je prečišćen hromatografijom na koloni (silika gel, elucioni gradijent: petrol etar/etil acetat: od 20/1 do 4/1). Željene frakcije su kombinovane i koncentrovane pod sniženim pritiskom. Ostatak je razblažen pomoću CH2Cl2(15 ml), zatim je dodat petrol etar/etil acetat (4:1, 200 ml). Smeša je koncentrovana do oko 150 ml, i čvrste supstance su se istaložile. Suspenzija je razblažena petrol etrom do oko 400 ml i mešana tokom 16 sati na 20°C. Smeša je filtrirana i čvrsta supstanca je isprana petrol etrom/etil acetatom (20/1, 100 ml). Čvrste supstance su sakupljene i osušene pod visokim vakuumom radi dobijanja čistog intermedijera 14 kao bele čvrste supstance (18,6 g, prinos 42% za 2 koraka). 25°C, the reaction mixture was concentrated under reduced pressure. The residue was partitioned between ethyl acetate (500 ml) and saturated aqueous NaHCO3 (500 ml). The layers were separated, and the aqueous phase was extracted with ethyl acetate (200 ml x 3). The combined organic layers were washed with brine (100 mL), dried over MgSO 4 , filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, elution gradient: CH2Cl2/ethyl acetate from 10/1 to 6/1). Fractions containing the desired intermediate 14 were combined and concentrated under reduced pressure. The residue (28 g, purity about 80%) was purified again by column chromatography (silica gel, elution gradient: petroleum ether/ethyl acetate: from 20/1 to 4/1). The desired fractions were combined and concentrated under reduced pressure. The residue was diluted with CH 2 Cl 2 (15 ml), then petroleum ether/ethyl acetate (4:1, 200 ml) was added. The mixture was concentrated to about 150 ml, and the solids were precipitated. The suspension was diluted with petroleum ether to about 400 ml and stirred for 16 hours at 20°C. The mixture was filtered and the solid was washed with petroleum ether/ethyl acetate (20/1, 100 mL). The solids were collected and dried under high vacuum to afford pure intermediate 14 as a white solid (18.6 g, 42% yield over 2 steps).

Primer A7 Example A7

Priprema intermedijera 15 Preparation of intermediates 15

[0383] [0383]

[0384] Intermedijer 1 (10,0 g, ≈28,6 mmol), TEA (12 ml, 85,7 mmol) i DMAP (0,70 g, 5,71 mmol) rastvoreni su u CH2Cl2(100 ml). Dodat je p-toluensulfonil hlorid (10,9 g, 57,1 mmol) na 0°C. Smeša je mešana na sobnoj temperaturi preko noći. U prethodni rastvor je dodata voda (100 ml). Vodeni sloj je ekstrahovan pomoću DCM (100 ml x 3). Kombinovani organski sloj je osušen iznad Na2SO4i koncentrovan do suva. Ostatak je prečišćen na fleš koloni (elucioni [0384] Intermediate 1 (10.0 g, ≈28.6 mmol), TEA (12 ml, 85.7 mmol) and DMAP (0.70 g, 5.71 mmol) were dissolved in CH 2 Cl 2 (100 ml). p-Toluenesulfonyl chloride (10.9 g, 57.1 mmol) was added at 0°C. The mixture was stirred at room temperature overnight. Water (100 ml) was added to the previous solution. The aqueous layer was extracted with DCM (100 ml x 3). The combined organic layer was dried over Na2SO4 and concentrated to dryness. The residue was purified on a flash column (elution

1 1

gradijent: petrol etar/etil acetat od 1/0 do 3/1). Frakcije proizvoda su sakupljene i rastvarač je uparen radi dobijanja intermedijera 15 kao žutog ulja (14,5 g, prinos 97%). gradient: petroleum ether/ethyl acetate from 1/0 to 3/1). The product fractions were collected and the solvent was evaporated to give intermediate 15 as a yellow oil (14.5 g, 97% yield).

[0385] Sledeći intermedijeri su pripremljeni reakcionim protokolom koji je analogan protokolu korišćenom za pripremu intermedijera 15 koristeći odgovarajuće polazne supstance (Tabela 3). [0385] The following intermediates were prepared by a reaction protocol analogous to the protocol used for the preparation of intermediate 15 using the appropriate starting substances (Table 3).

Tabela 3: Table 3:

Primer A8 Example A8

Priprema intermedijera 18 Preparation of intermediates 18

[0386] [0386]

1 4 1 4

[0387] Intermedijer 1 (100,0 g, teorijski 307 mmol) rastvoren je u 400 ml 1, 4-dioksana. Zatim je dodato 400 ml amonijum hidroksida (28-30% NH3baze). Smeša je mešana u zaptivenoj epruveti na 100°C tokom 20 sati. Smeša je ohlađena na sobnu temperaturu. Reakciona smeša je uparena pod vakuumom radi uklanjanja polovine rastvarača. Dodata je voda (200 ml) i ekstrahovana pomoću EtOAc (500 ml x 3). Kombinovani organski slojevi su isprani zasićenim vodenim rastvorom soli (200 ml x 2), osušeni i koncentrovani radi dobijanja intermedijera 18 kao bele čvrste supstance (93 g, prinos 93%). [0387] Intermediate 1 (100.0 g, theoretical 307 mmol) was dissolved in 400 ml of 1, 4-dioxane. Then 400 ml of ammonium hydroxide (28-30% NH3 base) was added. The mixture was stirred in a sealed tube at 100°C for 20 hours. The mixture was cooled to room temperature. The reaction mixture was evaporated under vacuum to remove half of the solvent. Water (200 mL) was added and extracted with EtOAc (500 mL x 3). The combined organic layers were washed with brine (200 mL x 2), dried and concentrated to afford intermediate 18 as a white solid (93 g, 93% yield).

[0388] Sledeći intermedijeri su pripremljeni reakcionim protokolom koji je analogan protokolu korišćenom za pripremu intermedijera 18 koristeći odgovarajuće polazne supstance (Tabela 4). [0388] The following intermediates were prepared by a reaction protocol analogous to the protocol used for the preparation of intermediate 18 using the appropriate starting substances (Table 4).

Tabela 4: Table 4:

1 1

Primer A9 Example A9

Priprema intermedijera 23 Preparation of intermediates 23

[0389] [0389]

Korak a: Step a:

[0390] [0390]

1 1

[0391] U rastvor intermedijera 21 (6,6 g, 9,75 mmol) u THF-u (130 ml) dodat je amonijak (28% u H2O, 65 ml) na sobnoj temperaturi. Reakciona smeša je mešana na 100°C (koristeći autoklav) tokom 16 sati. Reakciona smeša je ohlađena na sobnu temperaturu i uparena do suva pod sniženim pritiskom. Ostatak je prenet u vodu (100 ml) i DCM (100 ml) i mešan tokom 1 sata. Slojevi su razdvojeni, i vodeni sloj je ponovo ispran pomoću DCM (100 ml) kako bi se uklonile nečistoće. Vodeni sloj je filtriran, i filtrat je uparen do suva. Ostatak je prečišćen fleš hromatografijom na silika gelu (elucioni gradijent: DCM/MeOH od 95:5 do 90:10). Željene frakcije su sakupljene i rastvarač je uparen, dajući intermedijer 22 (3,4 g, sirova supstanca). Sirovi proizvod je neposredno korišćen u sledećem koraku reakcije bez daljeg prečišćavanja. [0391] To a solution of intermediate 21 (6.6 g, 9.75 mmol) in THF (130 mL) was added ammonia (28% in H2O, 65 mL) at room temperature. The reaction mixture was stirred at 100°C (using an autoclave) for 16 hours. The reaction mixture was cooled to room temperature and evaporated to dryness under reduced pressure. The residue was taken up in water (100 ml) and DCM (100 ml) and stirred for 1 hour. The layers were separated, and the aqueous layer was washed again with DCM (100 mL) to remove impurities. The aqueous layer was filtered, and the filtrate was evaporated to dryness. The residue was purified by flash chromatography on silica gel (elution gradient: DCM/MeOH from 95:5 to 90:10). The desired fractions were collected and the solvent was evaporated, giving intermediate 22 (3.4 g, crude). The crude product was directly used in the next reaction step without further purification.

Korak b: Step b:

[0392] [0392]

[0393] U smešu intermedijera 22 (1,0 g, sirova supstanca) u acetonu (32 ml) u jednoj porciji je dodat 2,2-dimetoksipropan (1,78 ml g, 14,5 mmol) i 4-metil benzensulfonska kiselina (0,61 g, 3,19 mmol) na sobnoj temperaturi. Smeša je mešana na 60°C tokom 3 sata. Smeša je ohlađena na sobnu temperaturu i deaktivirana sporim dodavanjem zasićenog NaHCO3(10 ml), a zatim ekstrahovana etil acetatom (50 ml x 5). Kombinovana organska faza je isprana zasićenim vodenim rastvorom soli (120 ml), osušena pomoću MgSO4, filtrirana i koncentrovana pod vakuumom, dajući intermedijer 23 (0,80 g, sirova supstanca). Sirovi proizvod je neposredno korišćen u sledećem koraku reakcije bez daljeg prečišćavanja. [0393] To a mixture of intermediate 22 (1.0 g, crude) in acetone (32 ml) was added 2,2-dimethoxypropane (1.78 ml g, 14.5 mmol) and 4-methyl benzenesulfonic acid (0.61 g, 3.19 mmol) in one portion at room temperature. The mixture was stirred at 60°C for 3 hours. The mixture was cooled to room temperature and quenched by slow addition of saturated NaHCO 3 (10 mL) and then extracted with ethyl acetate (50 mL x 5). The combined organic phase was washed with brine (120 mL), dried over MgSO 4 , filtered and concentrated in vacuo to give intermediate 23 (0.80 g, crude). The crude product was directly used in the next reaction step without further purification.

1 1

Primer A10 Example A10

Priprema intermedijera 24 Preparation of intermediates 24

[0394] [0394]

[0395] Intermedijer 18 (10,0 g, 32,6 mmol) rastvoren je u THF-u (200 ml). Zatim je dodat dimetil formamid dimetilacetal (DMF-DMA) (5,84 g, 49,0 mmol). Smeša je mešana na 60°C tokom 24 sata. Smeša je ohlađena na sobnu temperaturu, i rastvarač je koncentrovan pod vakuumom. Ostatak je trituriran sa EtOAc (200 ml) i vodom (100 ml). Organski sloj je razdvojen, vodeni sloj je ekstrahovan pomoću EtOAc (200 ml x 1), kombinovani organski sloj je ispran zasićenim vodenim rastvorom soli (50 ml), osušen iznad anhidrovanog Na2SO4, filtriran i koncentrovan radi dobijanja željenog intermedijera 24 kao žute čvrste supstance (10,5 g, prinos 85%) [0395] Intermediate 18 (10.0 g, 32.6 mmol) was dissolved in THF (200 mL). Dimethyl formamide dimethyl acetal (DMF-DMA) (5.84 g, 49.0 mmol) was then added. The mixture was stirred at 60°C for 24 hours. The mixture was cooled to room temperature, and the solvent was concentrated under vacuum. The residue was triturated with EtOAc (200 mL) and water (100 mL). The organic layer was separated, the aqueous layer was extracted with EtOAc (200 mL x 1), the combined organic layer was washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated to afford the desired intermediate 24 as a yellow solid (10.5 g, 85% yield).

[0396] Sledeći intermedijeri su pripremljeni reakcionim protokolom koji je analogan protokolu korišćenom za pripremu intermedijera 24 koristeći odgovarajuće polazne supstance (Tabela 5). [0396] The following intermediates were prepared by a reaction protocol analogous to the protocol used for the preparation of intermediate 24 using the appropriate starting substances (Table 5).

Tabela 5: Table 5:

1 1

Primer A 11 Example A 11

[0397] [0397]

Korak a: Step a:

[0398] [0398]

1 1

[0399] U smešu intermedijera 18 (88,0 g, 287 mmol) i imidazola (39,1 g, 575 mmol) u DMF-u (300,0 ml) u jednoj porciji je dodat TBDMSCl (52,0 g, 345 mmol) na 0°C u atmosferi N2. Reakciona smeša je mešana preko noći na sobnoj temperaturi. Nakon toga, dodata je voda (500 ml) i smeša je ekstrahovana pomoću EtOAc (800 ml x 3). Organski sloj je ispran zasićenim vodenim rastvorom soli (500 ml). Organska faza je zatim osušena pomoću anhidrovanog Na2SO4, filtrirana, i organska faza je koncentrovana pod vakuumom radi dobijanja sirovog proizvoda. Sirovi proizvod je prečišćen hromatografijom na koloni silika gela (elucioni gradijent: petrol etar/etil acetat 1:1). Željena frakcija je koncentrovana radi dobijanja intermedijera 27 kao ulja (120 g, prinos 96%). [0399] To a mixture of intermediate 18 (88.0 g, 287 mmol) and imidazole (39.1 g, 575 mmol) in DMF (300.0 ml) was added TBDMSCl (52.0 g, 345 mmol) in one portion at 0°C under N2 atmosphere. The reaction mixture was stirred overnight at room temperature. After that, water (500 mL) was added and the mixture was extracted with EtOAc (800 mL x 3). The organic layer was washed with saturated aqueous salt solution (500 ml). The organic phase was then dried over anhydrous Na 2 SO 4 , filtered, and the organic phase was concentrated under vacuum to give the crude product. The crude product was purified by silica gel column chromatography (elution gradient: petroleum ether/ethyl acetate 1:1). The desired fraction was concentrated to give intermediate 27 as an oil (120 g, yield 96%).

Korak b: Step b:

[0400] [0400]

[0401] U rastvor intermedijera 27 (12,4 g, ≈24,4 mmol) i DMAP (0,30 g, 2,44 mmol) u THF-u (50 ml) ukapavanjem je dodat (BOC)2O (13,3 g, 61,0 mmol) na sobnoj temperaturi. Reakciona smeša je mešana na sobnoj temperaturi tokom 3 sata. Zatim je ukapavanjem dodat 1 M rastvor TBAF u THF-u (24,4 ml, 24,4 ml). Reakciona smeša je mešana na rt tokom 18 sati. Reakciona smeša je sipana u 250 ml vode i ekstrahovana je etil acetatom (250 ml x 2). Organski sloj je ispran (voda) i zasićenim vodenim rastvorom soli, osušen pomoću Na2SO4i koncentrovan do suva. Ostatak je prečišćen fleš hromatografijom (elucija: etil acetat / heptan = 50/50). Željena frakcija je sakupljena, i ostatak je mešan u heptanu. Čvrsti proizvod je uklonjen filtracijom i osušen na rt pod sniženim pritiskom, dajući intermedijer 28 (10,2 g, prinos 83%) kao čvrsti proizvod. [0401] To a solution of intermediate 27 (12.4 g, ≈24.4 mmol) and DMAP (0.30 g, 2.44 mmol) in THF (50 ml) was added dropwise (BOC) 2 O (13.3 g, 61.0 mmol) at room temperature. The reaction mixture was stirred at room temperature for 3 hours. A 1 M solution of TBAF in THF (24.4 ml, 24.4 ml) was then added dropwise. The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was poured into 250 ml of water and extracted with ethyl acetate (250 ml x 2). The organic layer was washed (water) and brine, dried over Na2SO4 and concentrated to dryness. The residue was purified by flash chromatography (elution: ethyl acetate / heptane = 50/50). The desired fraction was collected, and the residue was stirred in heptane. The solid was removed by filtration and dried on the rt under reduced pressure to give intermediate 28 (10.2 g, 83% yield) as a solid.

1 1

[0402] Sledeći intermedijeri su pripremljeni reakcionim protokolom koji je analogan protokolu korišćenom za pripremu intermedijera 28 koristeći odgovarajuće polazne supstance (Tabela 23). [0402] The following intermediates were prepared by a reaction protocol analogous to the protocol used for the preparation of intermediate 28 using the appropriate starting substances (Table 23).

Tabela 23 Table 23

Primer A12 Example A12

Priprema intermedijera 29 Preparation of intermediates 29

[0403] [0403]

[0404] U reakcionu smešu intermedijera 24 (15,0 g, 41,7 mmol), Et3N (11,6 ml, 83,3 mmol) i DMAP (509 mg, 4,17 mmol) u DCM-u (200 ml) dodat je p-toluensulfonil hlorid (8,74 g, 45,9 mmol) na sobnoj temperaturi. Reakciona smeša je mešana na sobnoj temperaturi tokom 3 sata. U reakcionu smešu je dodata voda (100 ml), organski sloj je razdvojen, i vodeni sloj je [0404] To a reaction mixture of intermediate 24 (15.0 g, 41.7 mmol), Et3N (11.6 ml, 83.3 mmol) and DMAP (509 mg, 4.17 mmol) in DCM (200 ml) was added p-toluenesulfonyl chloride (8.74 g, 45.9 mmol) at room temperature. The reaction mixture was stirred at room temperature for 3 hours. Water (100 ml) was added to the reaction mixture, the organic layer was separated, and the aqueous layer was

1 1 1 1

ekstrahovan pomoću EtOAc (100 ml x 2). Kombinovani organski slojevi su isprani zasićenim vodenim rastvorom soli (100 ml), osušeni iznad anhidrovanog Na2SO4, filtrirani i koncentrovani radi dobijanja sirovog intermedijera 29 kao smeđe čvrste supstance koja je korišćena u sledećem koraku reakcije bez daljeg prečišćavanja. extracted with EtOAc (100 ml x 2). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated to afford crude intermediate 29 as a brown solid which was used in the next reaction step without further purification.

[0405] Sledeći intermedijeri su pripremljeni reakcionim protokolom koji je analogan protokolu korišćenom za pripremu intermedijera 29 koristeći odgovarajuće polazne supstance (Tabela 6) [0405] The following intermediates were prepared by a reaction protocol analogous to the protocol used for the preparation of intermediate 29 using the appropriate starting substances (Table 6)

Tabela 6: Table 6:

1 2 1 2

Primer A12b Example A12b

Priprema intermedijera 32 Preparation of intermediates 32

[0406] [0406]

[0407] Intermedijer 28 (4,5 g, 8,89 mmol), TEA (2,70 g, 26,6 mmol), DMAP (0,54 g, 4,4 mmol) i DCM (40 ml) mešani su u ledenom kupatilu. Ukapavanjem je dodat p-toluensulfonil hlorid (3,39 g, 17,8 mmol). Smeša je mešana na sobnoj temperaturi tokom 5 sati. Reakciona smeša je sipana u vodu i ekstrahovana DCM-om. Organski sloj je uparen i prečišćen fleš hromatografijom na silika gelu (eluent: 98% DCM 2% MeOH) radi dobijanja intermedijera 32 (5,6 g, prinos 95%). [0407] Intermediate 28 (4.5 g, 8.89 mmol), TEA (2.70 g, 26.6 mmol), DMAP (0.54 g, 4.4 mmol) and DCM (40 mL) were mixed in an ice bath. p-toluenesulfonyl chloride (3.39 g, 17.8 mmol) was added dropwise. The mixture was stirred at room temperature for 5 hours. The reaction mixture was poured into water and extracted with DCM. The organic layer was evaporated and purified by flash chromatography on silica gel (eluent: 98% DCM 2% MeOH) to give intermediate 32 (5.6 g, 95% yield).

Primer A13 Example A13

Priprema intermedijera 33 Preparation of intermediates 33

[0408] [0408]

1 1

[0409] U smešu intermedijera 1 (2,00 g, teorijski 6,18 mmol) u DCM-u (40 ml) dodat je Des-Martinov perjodinan (5,24 g, 12,36 mmol) u jednoj porciji na 0°C u atmosferi N2. Smeša je mešana na 0°C tokom 3 sata. U smešu je dodat Na2S2O3(4 g) u zasićenom NaHCO3(20 ml) i mešan tokom 10 min. Vodena faza je ekstrahovana DCM-om (20 ml x 3). Kombinovana organska faza je isprana zasićenim vodenim rastvorom soli (20 ml x 2), osušena anhidrovanim MgSO4, filtrirana i koncentrovana pod vakuumom radi dobijanja intermedijera 33 (1,80 g, sirova supstanca) kao svetložute gume. Sirovi proizvod je neposredno korišćen u sledećem koraku reakcije bez daljeg prečišćavanja. [0409] To a mixture of intermediate 1 (2.00 g, theoretical 6.18 mmol) in DCM (40 ml) was added Des-Martin's periodinane (5.24 g, 12.36 mmol) in one portion at 0°C under N 2 . The mixture was stirred at 0°C for 3 hours. Na2S2O3 (4 g) in saturated NaHCO3 (20 ml) was added to the mixture and stirred for 10 min. The aqueous phase was extracted with DCM (20 ml x 3). The combined organic phase was washed with brine (20 mL x 2), dried over anhydrous MgSO 4 , filtered and concentrated under vacuum to afford intermediate 33 (1.80 g, crude) as a pale yellow gum. The crude product was directly used in the next reaction step without further purification.

[0410] Sledeći intermedijeri su pripremljeni reakcionim protokolom koji je analogan protokolu korišćenom za pripremu intermedijera 33 koristeći odgovarajuće polazne supstance (Tabela 7). [0410] The following intermediates were prepared by a reaction protocol analogous to the protocol used for the preparation of intermediate 33 using the appropriate starting substances (Table 7).

Tabela 7: Table 7:

1 4 1 4

Primer A14 Example A14

Priprema intermedijera 37 Preparation of intermediates 37

[0411] [0411]

[0412] U rastvor intermedijera 33 (6,5 g, sirova supstanca, ≈15,46 mmol) u THF-u (200 ml) u kapima je dodat MeMgBr (1 M, 18,55 ml, 18,55 mmol) na -78°C u atmosferi N2. Smeša je [0412] To a solution of intermediate 33 (6.5 g, crude substance, ≈15.46 mmol) in THF (200 ml) was added MeMgBr (1 M, 18.55 ml, 18.55 mmol) dropwise at -78°C under N2 atmosphere. It's mixed

1 1

mešana preko noći na sobnoj temperaturi u atmosferi N2. Reakciona smeša je koncentrovana pod vakuumom radi dobijanja sirovog proizvoda kao žute čvrste supstance. Sirovi proizvod je prečišćen hromatografijom na koloni (elucioni gradijent: petrol etar/EtOAc od 40:1 do 10:1). Željene frakcije su sakupljene i rastvarač je uparen radi dobijanja intermedijera 37 kao svetložutog ulja (700 mg sirovo; i 3 g sirovo sa više nečistoća). stirred overnight at room temperature under N2 atmosphere. The reaction mixture was concentrated under vacuum to give the crude product as a yellow solid. The crude product was purified by column chromatography (elution gradient: petroleum ether/EtOAc from 40:1 to 10:1). The desired fractions were collected and the solvent was evaporated to give intermediate 37 as a pale yellow oil (700 mg crude; and 3 g crude with more impurities).

Primer A15 Example A15

Priprema intermedijera 38 Preparation of intermediates 38

Postupak 1 Procedure 1

[0413] [0413]

[0414] U smešu metiltrifenil fosfonijum bromida (4,87 g, 13,62 mmol) u THF-u (500 ml) ukapavanjem je dodat t-BuOK (11,4 ml, 1 M u THF-u, 1,27 g, 11,35 mmol,) na 0°C u atmosferi N2. Suspenzija je postala jarko žuta i mešana je na 0°C tokom 0,5 h i zatim zagrejana na 25°C tokom 0,5 h. Smeša je ohlađena na -40°C. Rastvor intermedijera 35 (1,46 g, teorijski 4,54 mmol) u THF-u (130,0 ml) dodat je ukapavanjem i zatim mešan na -20°C tokom 1 h, nakon toga, smeša je zagrevana na 25°C tokom 2 h. U smešu je dodat zasićeni NH4Cl (300 ml), i mešana je tokom 10 min. Slojevi su razdvojeni, i vodena faza je ekstrahovana DCM-om (300 ml x 2). Kombinovana organska faza je isprana zasićenim vodenim rastvorom soli (500 ml), osušena anhidrovanim MgSO4, filtrirana i koncentrovana pod vakuumom. Ostatak je prečišćen hromatografijom na silika gelu (ISCO®; 80 g SepaFlash® fleš kolona silika gela, elucioni gradijent: od 0 do 15% etil acetat/petrol etar). Željene frakcije su sakupljene, i rastvarač je uparen. Intermedijer 38 je dobijen kao beličasta čvrsta supstanca (530 mg, prinos 36%). [0414] To a mixture of methyltriphenyl phosphonium bromide (4.87 g, 13.62 mmol) in THF (500 mL) was added dropwise t-BuOK (11.4 mL, 1 M in THF, 1.27 g, 11.35 mmol) at 0°C under N2 atmosphere. The suspension turned bright yellow and was stirred at 0°C for 0.5 h and then warmed to 25°C for 0.5 h. The mixture was cooled to -40°C. A solution of intermediate 35 (1.46 g, theoretical 4.54 mmol) in THF (130.0 mL) was added dropwise and then stirred at -20 °C for 1 h, after which the mixture was warmed to 25 °C for 2 h. Saturated NH 4 Cl (300 ml) was added to the mixture and stirred for 10 min. The layers were separated, and the aqueous phase was extracted with DCM (300 ml x 2). The combined organic phase was washed with brine (500 mL), dried over anhydrous MgSO4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (ISCO®; 80 g SepaFlash® silica gel flash column, elution gradient: from 0 to 15% ethyl acetate/petroleum ether). The desired fractions were collected, and the solvent was evaporated. Intermediate 38 was obtained as an off-white solid (530 mg, 36% yield).

1 1

[0415] Sledeći intermedijeri su pripremljeni reakcionim protokolom koji je analogan protokolu korišćenom za pripremu intermedijera 38 (postupak 1) koristeći odgovarajuće polazne supstance (Tabela 8). [0415] The following intermediates were prepared by a reaction protocol analogous to the protocol used for the preparation of intermediate 38 (method 1) using the appropriate starting substances (Table 8).

Tabela 8: Table 8:

Postupak 2 Step 2

[0416] [0416]

1 1

[0417] Rastvor intermedijera 35 (10,0 g, teorijski 31,1 mmol) u THF-u (100 ml) ukapavanjem je dodavan pod atmosferom N2tokom 30 minuta u rastvor bis(jodcink)metana u THF-u (180 ml, 0,31 M, 55,9 mmol, pripremljen prema proceduri koja je opisana u publikaciji Tetrahedron 2002, 58, 8255-8262), mešanje je nastavljeno do potpune konverzije (približno 2 sata). Reakciona smeša je deaktivirana sporim dodavanjem zasićenog vodenog rastvora NH4Cl, prilikom čega je uočen nastanak soli. Pre ekstrakcije (EtOAc, 2 x 200 ml), soli su ponovo rastvorene dodavanjem vodenog rastvora amonijaka (25%). Kombinovane organske faze su isprane vodenim rastvorom natrijum bisulfita i zasićenim vodenim rastvorom soli, osušene pomoću anhidrovanog MgSO4, filtrirane i koncentrovane pod vakuumom. Ostatak je prečišćen hromatografijom na silika gelu (eluent: dihlormetan/EtOAc 95/5) radi dobijanja intermedijera 38 kao beličaste čvrste supstance (6,9 g, 66%). [0417] A solution of intermediate 35 (10.0 g, theoretical 31.1 mmol) in THF (100 ml) was added dropwise under N2 over 30 minutes to a solution of bis(iodozinc)methane in THF (180 ml, 0.31 M, 55.9 mmol), prepared according to the procedure described in the publication Tetrahedron 2002, 58, 8255-8262), stirring was continued until complete conversion (approximately 2 hours). The reaction mixture was deactivated by slowly adding a saturated aqueous solution of NH4Cl, during which salt formation was observed. Prior to extraction (EtOAc, 2 x 200 ml), the salts were redissolved by addition of aqueous ammonia (25%). The combined organic phases were washed with aqueous sodium bisulfite and brine, dried over anhydrous MgSO 4 , filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (eluent: dichloromethane/EtOAc 95/5) to give intermediate 38 as an off-white solid (6.9 g, 66%).

Postupak 3 Procedure 3

Korak 1 Step 1

Priprema intermedijera 408 Preparation of intermediate 408

[0418] [0418]

[0419] Acetilacetonatobis(etilen)rodijum(I) (0,837 g, 3,24 mmol) i (R)-N,N-dimetildinafto[2,1-D:1',2'-F][1,3,2]dioksafosfepin-4-amin (2,91 g, 8,11 mmol) rastvoreni su u [0419] Acetylacetonatobis(ethylene)rhodium(I) (0.837 g, 3.24 mmol) and (R)-N,N-dimethyldinaphtho[2,1-D:1',2'-F][1,3,2]dioxaphosphepin-4-amine (2.91 g, 8.11 mmol) were dissolved in

1 1

EtOH (625 ml) u atmosferi azota. Smeša je mešana na sobnoj temperaturi i produvana gasovitim azotom tokom 15 minuta. Zatim su dodati (-)-(3AR,6AR)-3A,6A-dihidro-2,2-dimetil-4H-ciklopenta-1,3-dioksol-4-on (25 g, 162,16 mmol) i kalijum vinil trifluorborat (45,73 g, 324,33 mmol), i reakciona smeša je zatim mešana i refluktovana tokom 4 sata. Reakciona smeša (suspenzija) je ohlađena na sobnu temperaturu. Talog je uklonjen filtracijom preko sloja celita i ispran etanolom. Rastvarači iz filtrata su uklonjeni uparavanjem. 1 l heptana je dodat u ostatak. Dobijena suspenzija je filtrirana preko sloja celita i isprana smešom heptana, što daje tamnosmeđi čvrsti ostatak. Filtrat je tri puta ispran sa 300 ml NH4OH, ispran zasićenim vodenim rastvorom soli, osušen pomoću MgSO4, filtriran, i rastvarači iz filtrata su upareni, dajući intermedijer 408 (16,18 g, prinos 51%). EtOH (625 mL) under nitrogen. The mixture was stirred at room temperature and purged with nitrogen gas for 15 minutes. Then (-)-(3AR,6AR)-3A,6A-dihydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-one (25 g, 162.16 mmol) and potassium vinyl trifluoroborate (45.73 g, 324.33 mmol) were added, and the reaction mixture was then stirred and refluxed for 4 hours. The reaction mixture (suspension) was cooled to room temperature. The precipitate was removed by filtration over a pad of celite and washed with ethanol. Solvents from the filtrate were removed by evaporation. 1 L of heptane was added to the residue. The resulting suspension was filtered through a pad of celite and washed with a heptane mixture to give a dark brown solid residue. The filtrate was washed three times with 300 mL of NH 4 OH, washed with brine, dried over MgSO 4 , filtered, and the solvents from the filtrate were evaporated to give intermediate 408 (16.18 g, 51% yield).

Korak 2 Step 2

Priprema intermedijera 409 Preparation of intermediates 409

[0420] [0420]

[0421] Rastvor intermedijera 408 (16,18 g, 82,58 mmol) u THF-u (200 ml) ukapavanjem je uz mešanje dodat u 1 M rastvor litijum aluminijum hidrida u THF-u (24,78 ml, 1 M, 24,78 mmol) u THF-u (400 ml) na -78°C u atmosferi azota. Reakciona smeša je mešana na -78°C u atmosferi azota tokom 30 minuta. Reakcija je deaktivirana ukapavanjem acetona (6,1 ml), zatim 50 ml vode na -78°C. Nakon dodavanja, reakciona smeša je ostavljena da se zagreje na sobnu temperaturu, a zatim je dodato 400 ml EtOAc. Smeša je žustro tresena. Organski sloj je razdvojen, tri puta ispran vodom, ispran zasićenim vodenim rastvorom soli, osušen pomoću MgSO4, filtriran, i rastvarači iz filtrata su upareni. Ostatak je rastvoren u etil acetatu i prečišćen na koloni SiO2, tip Grace Reveleris SRC, 80 g, Si 40, na Armen Spot II Ultimate sistemu za prečišćavanje, koristeći etil acetat i heptan kao eluent sa gradijentom koji polazi od 100% [0421] A solution of intermediate 408 (16.18 g, 82.58 mmol) in THF (200 mL) was added dropwise with stirring to a 1 M solution of lithium aluminum hydride in THF (24.78 mL, 1 M, 24.78 mmol) in THF (400 mL) at -78°C under a nitrogen atmosphere. The reaction mixture was stirred at -78°C under a nitrogen atmosphere for 30 minutes. The reaction was quenched by dropping acetone (6.1 ml) followed by 50 ml water at -78°C. After the addition, the reaction mixture was allowed to warm to room temperature and then 400 ml of EtOAc was added. The mixture is vigorously shaken. The organic layer was separated, washed three times with water, brine, dried over MgSO 4 , filtered, and the solvents from the filtrate were evaporated. The residue was dissolved in ethyl acetate and purified on a SiO2 column, Grace Reveleris SRC type, 80 g, Si 40, on an Armen Spot II Ultimate purification system, using ethyl acetate and heptane as eluent with a gradient starting at 100%

1 1

heptana i završava se sa 50% heptana i 50% etil acetata. Frakcije koje sadrže proizvod su kombinovane i rastvarači su upareni, dajući intermedijer 409 (10,77 g, prinos 71%). heptane and finished with 50% heptane and 50% ethyl acetate. Fractions containing the product were combined and the solvents were evaporated, giving intermediate 409 (10.77 g, 71% yield).

Korak 3 Step 3

Priprema intermedijera 410 Preparation of intermediate 410

[0422] [0422]

[0423] Rastvor Tf2O (13,31 ml, 1,71 g/ml, 80,93 mmol) u DCM-u, anhidrovani (60 ml), dodat je u smešu intermedijera 409 (9,94 g, 53,95 mmol) i anhidrovanog piridina (85 ml) u anhidrovanom DCM-u (140 ml) na 0°C. Reakciona smeša je mešana tokom 30 minuta i zatim je dodato 75 ml hladne vode. Slojevi su razdvojeni, i organski sloj je tri puta ispran sa 75 ml vode, osušen pomoću MgSO4, filtriran, i rastvarači su upareni, i zajedno upareni sa 200 ml toluena. Ostatak je rastvoren u heptanu i etil acetatu i prečišćen na koloni SiO2, tip Grace Reveleris SRC, 40 g, Si 40, na Armen Spot II Ultimate sistemu za prečišćavanje, koristeći etil acetat i heptan kao eluent sa gradijentom koji polazi od 100% heptana i završava se sa 50% heptana i 50% etil acetata. Frakcije koje sadrže proizvod su kombinovane i rastvarači su upareni, dajući intermedijer 410 (13,0 g, prinos 67%). [0423] A solution of Tf2O (13.31 ml, 1.71 g/ml, 80.93 mmol) in anhydrous DCM (60 ml) was added to a mixture of intermediate 409 (9.94 g, 53.95 mmol) and anhydrous pyridine (85 ml) in anhydrous DCM (140 ml) at 0°C. The reaction mixture was stirred for 30 minutes and then 75 ml of cold water was added. The layers were separated, and the organic layer was washed three times with 75 mL of water, dried over MgSO 4 , filtered, and the solvents were evaporated, and coevaporated with 200 mL of toluene. The residue was dissolved in heptane and ethyl acetate and purified on a SiO2 column, Grace Reveleris SRC type, 40 g, Si 40, on an Armen Spot II Ultimate purification system, using ethyl acetate and heptane as eluent with a gradient starting at 100% heptane and ending with 50% heptane and 50% ethyl acetate. Fractions containing the product were combined and the solvents were evaporated, giving intermediate 410 (13.0 g, 67% yield).

Korak 4 Step 4

Priprema intermedijera 411 Preparation of intermediate 411

[0424] [0424]

2 2

[0425] Smeša 4-hlor-7H-pirolo[2,3-D]pirimidina (100 g, 651 mmol) i KOtBu (73,07 g, 651 mmol) u THF-u (1 l) mešana je na sobnoj temperaturi tokom 45 minuta dok nije dobijen bistar rastvor. Rastvarači su upareni. Ostatak je trituriran u DIPE. Bele čvrste supstance su uklonjene filtracijom i osušene pod vakuumom na 30°C, dajući intermedijer 411 (112,6 g, prinos 90%). [0425] A mixture of 4-chloro-7H-pyrrolo[2,3-D]pyrimidine (100 g, 651 mmol) and KOtBu (73.07 g, 651 mmol) in THF (1 L) was stirred at room temperature for 45 min until a clear solution was obtained. Solvents are evaporated. The rest was triturated in DIPE. The white solids were removed by filtration and dried under vacuum at 30 °C to give intermediate 411 (112.6 g, 90% yield).

Korak 5 Step 5

Priprema intermedijera 38 Preparation of intermediates 38

[0426] [0426]

[0427] Rastvor intermedijera 410 (13 g, 41,1 mmol) u DMF-u (50 ml) u kapima je uz mešanje dodat u rastvor intermedijera 411 (7,88 g, 41,1 mmol) u DMF-u (150 ml) na 0°C. Nakon dodavanja, reakciona smeša je ostavljena da se zagreje na sobnu temperaturu i zatim je mešana tokom 18 sati. Dodata je još jedna količina intermedijera 411 (1,57 g, 8,22 mmol). Reakciona smeša je mešana na sobnoj temperaturi tokom 2 sata. Reakciona smeša je sipana u laboratorijsku čašu sa ledom i vodom (∼0,5 l). Dobijena suspenzija je mešana tokom 2 sata i zatim filtrirana. Ostatak je tri puta ispran vodom i zatim osušen pod vakuumom na 50°C, dajući intermedijer 38 kao belu čvrstu supstancu (8,75 g, prinos 65%). [0427] A solution of Intermediate 410 (13 g, 41.1 mmol) in DMF (50 mL) was added dropwise to a solution of Intermediate 411 (7.88 g, 41.1 mmol) in DMF (150 mL) at 0°C with stirring. After the addition, the reaction mixture was allowed to warm to room temperature and then stirred for 18 hours. Another amount of intermediate 411 (1.57 g, 8.22 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into a laboratory beaker with ice and water (∼0.5 l). The resulting suspension was stirred for 2 hours and then filtered. The residue was washed three times with water and then dried under vacuum at 50 °C to give intermediate 38 as a white solid (8.75 g, 65% yield).

2 1 2 1

Primer A 54 Example A 54

Priprema intermedijera 433 Preparation of intermediates 433

[0428] [0428]

[0429] Rastvor intermedijera 38 (18,3 g, 57,22 mmol) u smeši vodenog amonijaka (25%, 100 ml) i THF-a (100 ml) zagrevan je u zaptivenom metalnom sudu za rad pod pritiskom na 110°C do potpune konverzije (∼16 h). Reakciona smeša je ostavljena da se ohladi na sobnu temperaturu, nakon čega su dodati etil acetat i zasićeni vodeni rastvor soli. Oba sloja su razdvojena, a vodeni sloj je jednom ekstrahovan etil acetatom. Kombinovane organske faze su isprane zasićenim vodenim rastvorom soli, osušene anhidrovanim MgSO4, filtrirane i koncentrovane pod vakuumom radi dobijanja intermedijera 433 kao svetložute čvrste supstance (17,2 g, 100%) koja je korišćena u sledećem koraku reakcije bez daljeg prečišćavanja. [0429] A solution of intermediate 38 (18.3 g, 57.22 mmol) in a mixture of aqueous ammonia (25%, 100 ml) and THF (100 ml) was heated in a sealed metal pressure vessel at 110 °C until complete conversion (∼16 h). The reaction mixture was allowed to cool to room temperature, after which ethyl acetate and saturated aqueous salt solution were added. Both layers were separated, and the aqueous layer was extracted once with ethyl acetate. The combined organic phases were washed with brine, dried over anhydrous MgSO 4 , filtered and concentrated in vacuo to afford intermediate 433 as a light yellow solid (17.2 g, 100%) which was used in the next reaction step without further purification.

[0430] Sledeći intermedijeri su pripremljeni reakcionim protokolom koji je analogan protokolu korišćenom za pripremu intermedijera 433 koristeći odgovarajuće polazne supstance (Tabela 24 [0430] The following intermediates were prepared by a reaction protocol analogous to the protocol used for the preparation of intermediate 433 using the appropriate starting substances (Table 24

Tabela 24: Table 24:

2 2 2 2

Primer A16 Example A16

Priprema intermedijera 41 Preparation of intermediates 41

[0431] [0431]

[0432] U rastvor kalijum terc-butoksida (1,28 g; 11,4 mmol) u THF-u (30 ml) na -78°C dodat je rastvor dimetil (1-diazo-2-oksopropil)fosfonata (1,72 g; 11,4 mmol) u THF-u (5 ml). Rastvor je mešan tokom 5 min i zatim je dodat rastvor intermedijera 33 (1,90 g; teorijski 5,87 mmol) u THF-u (20 ml). Rastvor je ostavljen da se zagreje na sobnu temperaturu, i mešan je na sobnoj temperaturi tokom 15 minuta. Dodati su voda i EtOAc, organski sloj je razdvojen, osušen iznad MgSO4, filtriran i uparen pod vakuumom. Ostaci su prečišćeni pomoću preparativne LC (nepravilni SiOH 15-40 µm, 80 g Grace, DCM za nanošenje, mobilna faza gradijent elucije: [0432] To a solution of potassium tert-butoxide (1.28 g; 11.4 mmol) in THF (30 ml) at -78°C was added a solution of dimethyl (1-diazo-2-oxopropyl)phosphonate (1.72 g; 11.4 mmol) in THF (5 ml). The solution was stirred for 5 min and then a solution of intermediate 33 (1.90 g; theoretical 5.87 mmol) in THF (20 mL) was added. The solution was allowed to warm to room temperature, and was stirred at room temperature for 15 minutes. Water and EtOAc were added, the organic layer was separated, dried over MgSO 4 , filtered and evaporated in vacuo. The residues were purified by preparative LC (irregular SiOH 15-40 µm, 80 g Grace, DCM loading, mobile phase gradient elution:

2 2

heptan: 10% MeOH u EtOAc od 90:10 do 70:30). Željene frakcije su sakupljene, i rastvarač je uparen radi dobijanja intermedijera 41 kao bezbojnog ulja (1,08 g, prinos 58%). heptane: 10% MeOH in EtOAc from 90:10 to 70:30). The desired fractions were collected, and the solvent was evaporated to give intermediate 41 as a colorless oil (1.08 g, 58% yield).

Primer A17 Example A17

Priprema intermedijera 43 Preparation of intermediates 43

[0433] [0433]

[0434] U rastvor intermedijera 42 (9,2 g, 34,114 mmol) u acetonu (100 ml) dodat je 2,2-dimetoksipropan (7,1 g, 68,118 mmol) i p-TSA (1,8 g, 10,184 mmol). Reakciona smeša je mešana preko noći na sobnoj temperaturi. Reakciona smeša je tretirana vodenim NaHCO3(pH do 7-8), zatim koncentrovana pod sniženim pritiskom. Dobijeni ostatak je razblažen vodom (100 ml) i ekstrahovan etil acetatom (100 ml x 3). Organski sloj je osušen i koncentrovan pod sniženim pritiskom. Sirovi proizvod je prečišćen hromatografijom na silika gelu (elucioni gradijent: petrol etar/etil acetat od 8/1 do 2/1). Željene frakcije su sakupljene, i rastvarač je uparen radi dobijanja intermedijera 43 kao bledožute čvrste supstance (9,5 g, prinos 90%). [0434] To a solution of intermediate 42 (9.2 g, 34.114 mmol) in acetone (100 ml) was added 2,2-dimethoxypropane (7.1 g, 68.118 mmol) and p-TSA (1.8 g, 10.184 mmol). The reaction mixture was stirred overnight at room temperature. The reaction mixture was treated with aqueous NaHCO3 (pH to 7-8), then concentrated under reduced pressure. The resulting residue was diluted with water (100 ml) and extracted with ethyl acetate (100 ml x 3). The organic layer was dried and concentrated under reduced pressure. The crude product was purified by chromatography on silica gel (elution gradient: petroleum ether/ethyl acetate from 8/1 to 2/1). The desired fractions were collected, and the solvent was evaporated to give intermediate 43 as a pale yellow solid (9.5 g, 90% yield).

Primer A18 Example A18

Priprema intermedijera 44 Preparation of intermediates 44

[0435] [0435]

2 4 2 4

[0436] Rastvor intermedijera 1 (2,00 g, teorijski 6,18 mmol) u DCM-u (30,00 ml) ukapavanjem je dodat u suspenziju Des-Martinovog perjodinana (3,14 g, 7,41 mmol) u DCM-u (30,00 ml) na 0°C u atmosferi N2. Reakciona smeša je ostavljena da se zagreje na sobnu temperaturu i mešana je do završetka oksidacije (2 sata). Nakon toga, dodati su MeOH (60 ml) i tozilhidrazid (1,50 g, 8,03 mmol) i mešanje je nastavljeno još 3 sata. U reakcionu smešu su dodati voda i etil acetat, organska faza je razdvojena i isprana zasićenim Na2CO3, osušena anhidrovanim MgSO4, filtrirana i koncentrovana pod vakuumom. Sirovi proizvod je prečišćen hromatografijom na koloni silika gela (elucioni gradijent: dihlormetan / metanol od 100:0 do 98,5:1,5). Željene frakcije su sakupljene, i rastvarač je uparen radi dobijanja intermedijera 44 kao belog praha (2,60 g, prinos 70%; (E)). [0436] A solution of intermediate 1 (2.00 g, theoretical 6.18 mmol) in DCM (30.00 ml) was added dropwise to a suspension of Des-Martin periodinane (3.14 g, 7.41 mmol) in DCM (30.00 ml) at 0°C under N2 atmosphere. The reaction mixture was allowed to warm to room temperature and was stirred until oxidation was complete (2 hours). After that, MeOH (60 mL) and tosylhydrazide (1.50 g, 8.03 mmol) were added and stirring was continued for another 3 h. Water and ethyl acetate were added to the reaction mixture, the organic phase was separated and washed with saturated Na2CO3, dried over anhydrous MgSO4, filtered and concentrated under vacuum. The crude product was purified by silica gel column chromatography (elution gradient: dichloromethane/methanol from 100:0 to 98.5:1.5). The desired fractions were collected, and the solvent was evaporated to give intermediate 44 as a white powder (2.60 g, 70% yield; (E)).

[0437] Sledeći intermedijeri su pripremljeni reakcionim protokolom koji je analogan protokolu korišćenom za pripremu intermedijera 44 koristeći odgovarajuće polazne supstance (Tabela 25 [0437] The following intermediates were prepared by a reaction protocol analogous to the protocol used for the preparation of intermediate 44 using the appropriate starting substances (Table 25

Tabela 25 Table 25

2 2

Primer A 55 Example A 55

Priprema intermedijera 224 Preparation of intermediates 224

[0438] [0438]

Korak 1: Step 1:

Priprema intermedijera 222 Preparation of intermediates 222

[0439] DIAD (7,6 ml, 38,4 mmol, 2,5 ekv.) dodat je u rastvor intermedijera 2 (5,0 g, 15,3 mmol, 1,0 ekv.), trifenilfosfina (10,0 g, 38,4 mmol, 2,5 ekv.) i aceton cijanohidrina (5,6 ml, 61,4 mmol, 4,0 ekv.) u anhidrovanom THF-u (75 ml) na r.t. Reakciona smeša je mešana tokom 1 sata i zatim koncentrovana pod vakuumom. Sirovi proizvod je prečišćen fleš hromatografijom na normalnoj fazi koristeći heptan i DCM kao eluent (kolona SiO2, gradijent: [0439] DIAD (7.6 mL, 38.4 mmol, 2.5 equiv.) was added to a solution of intermediate 2 (5.0 g, 15.3 mmol, 1.0 equiv.), triphenylphosphine (10.0 g, 38.4 mmol, 2.5 equiv.), and acetone cyanohydrin (5.6 mL, 61.4 mmol, 4.0 equiv.) in anhydrous to THF (75 ml) at r.t. The reaction mixture was stirred for 1 hour and then concentrated under vacuum. The crude product was purified by flash chromatography on a normal phase using heptane and DCM as eluent (SiO2 column, gradient:

2 2

50% do 100% DCM, izokratski 100% DCM) a zatim preparativnom reversno faznom fleš hromatografijom koristeći acetonitril i vodu sa 0,2% NH4HCO3kao eluent radi dobijanja intermedijera 222 kao belog čvrstog proizvoda (2,8 g, 8,5 mmol, prinos 55%) 50% to 100% DCM, isocratic 100% DCM) followed by preparative reverse-phase flash chromatography using acetonitrile and water with 0.2% NH4HCO3 as eluent to afford intermediate 222 as a white solid (2.8 g, 8.5 mmol, 55% yield).

Korak 2: Step 2:

Priprema intermedijera 223 i intermedijera 224 Preparation of intermediate 223 and intermediate 224

[0440] Rastvor intermedijera 222 (1,54 g, 4,6 mmol, 1 ekv.) u anhidrovanom DCM-u osušen je preko noći iznad molekulskih sita i filtriran. Filtrat je ohlađen na -78°C i zatim je ukapavanjem dodat 1 M DIBAH u DCM-u (4,6 ml, 4,6 mmol, 1 ekv.). Reakciona smeša je mešana tokom 1 sata na -78°C, zatim je dodato još 1 M DIBAH u DCM-u (0,46 ml, 0,46 mmol, 0,1 ekv.) i mešano tokom još 1,5 sati, zatim je deaktivirana natrijum acetatom (4,2 g, 51,2 mmol, 11,1 ekv.) i sirćetnom kiselinom (4,2 ml, 73,4 ml, 16,0 ekv.) u smeši voda/THF (57 ml/12 ml). Nakon deaktivacije, kupatilo za hlađenje je uklonjeno i smeša je mešana sve dok se sav led nije istopio. Slojevi su razdvojeni, i vodena faza je zatim ekstrahovana dva puta DCM-om (30 ml). Organske faze su kombinovane, dva puta isprane zasićenim vodenim rastvorom soli, osušene iznad MgSO4i filtrirane. U dobijeni filtrat koji sadrži intermedijer 223 dodat je MeOH (50 ml), p-toluensulfonil hidrazid (1,1 g, 6,0 mmol, 3 ekv.) i mešan je na r.t. tokom 40 minuta. Reakciona smeša je tri puta isprana zas. NaHCO3, dva puta zasićenim vodenim rastvorom soli, osušena iznad MgSO4, filtrirana i koncentrovana pod vakuumom. Sirovi proizvod je prečišćen fleš hromatografijom na normalnoj fazi koristeći heptan i EtOAc kao eluent (gradijent: 40% do 60% EtOAc radi dobijanja sirovog proizvoda. Smeša je dalje prečišćena fleš hromatografijom na normalnoj fazi koristeći EtOAc i heptan kao eluent (kolona SiO2, gradijent: 40% do 60% EtOAc) radi dobijanja intermedijera 224 (0,5 g, 0,6 mmol, prinos: 14%). [0440] A solution of intermediate 222 (1.54 g, 4.6 mmol, 1 eq.) in anhydrous DCM was dried overnight over molecular sieves and filtered. The filtrate was cooled to -78°C and then 1 M DIBAH in DCM (4.6 mL, 4.6 mmol, 1 equiv) was added dropwise. The reaction mixture was stirred for 1 h at -78°C, then additional 1 M DIBAH in DCM (0.46 mL, 0.46 mmol, 0.1 eq) was added and stirred for another 1.5 h, then quenched with sodium acetate (4.2 g, 51.2 mmol, 11.1 eq) and acetic acid (4.2 mL, 73.4 mL, 11.1 eq). 16.0 equiv) in water/THF (57 ml/12 ml). After deactivation, the cooling bath was removed and the mixture was stirred until all the ice had melted. The layers were separated, and the aqueous phase was then extracted twice with DCM (30 mL). The organic phases were combined, washed twice with saturated aqueous salt solution, dried over MgSO 4 and filtered. To the resulting filtrate containing intermediate 223 was added MeOH (50 ml), p-toluenesulfonyl hydrazide (1.1 g, 6.0 mmol, 3 eq.) and stirred at r.t. during 40 minutes. The reaction mixture was washed three times with sat. NaHCO3, twice saturated aqueous brine, dried over MgSO4, filtered and concentrated in vacuo. The crude product was purified by flash chromatography on the normal phase using heptane and EtOAc as eluent (gradient: 40% to 60% EtOAc to give the crude product. The mixture was further purified by flash chromatography on the normal phase using EtOAc and heptane as eluent (SiO2 column, gradient: 40% to 60% EtOAc) to give intermediate 224 (0.5 g, 0.6 mmol, yield: 14%).

Primer A19 Example A19

Priprema intermedijera 45 Preparation of intermediates 45

[0441] [0441]

2 2

[0442] Intermedijer 1 (300 mg, teorijski 0,921 mmol), 7-hinolinol (160 mg, 1,11 mmol) i polimerno vezani trifenil fosfin (∼3 mmol/g nanetog trifenil fosfina, 0,8 g, 2,4 mmol) mešani su u anhidrovanom THF-u (12 ml) u atmosferi N2. Nakon toga, ukapavanjem je dodat DIAD (0,465 g, 2,30 mmol) na 0°C. Smeša je mešana na sobnoj temperaturi tokom 12 sati u atmosferi N2. Reakciona smeša je filtrirana kroz sloj dijatomejske zemlje. Ostatak je ispran pomoću MeOH. Filtrat je koncentrovan pod vakuumom. Ostatak je prečišćen hromatografijom na koloni silika gela (eluent: petrol etar/etil acetat od 10/1 do 3/1). Željene frakcije su sakupljene, i rastvarač je uparen radi dobijanja sirovog intermedijera 45 kao ulja (342 mg). [0442] Intermediate 1 (300 mg, theoretical 0.921 mmol), 7-quinolinol (160 mg, 1.11 mmol) and polymer bound triphenyl phosphine (∼3 mmol/g applied triphenyl phosphine, 0.8 g, 2.4 mmol) were mixed in anhydrous THF (12 mL) under N2 atmosphere. After that, DIAD (0.465 g, 2.30 mmol) was added dropwise at 0 °C. The mixture was stirred at room temperature for 12 hours under N2 atmosphere. The reaction mixture was filtered through a layer of diatomaceous earth. The residue was washed with MeOH. The filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate from 10/1 to 3/1). The desired fractions were collected, and the solvent was evaporated to give crude intermediate 45 as an oil (342 mg).

[0443] Sledeći intermedijeri su pripremljeni reakcionim protokolom koji je analogan protokolu korišćenom za pripremu intermedijera 45 koristeći odgovarajuće polazne supstance (Tabela 9). [0443] The following intermediates were prepared by a reaction protocol analogous to the protocol used for the preparation of intermediate 45 using the appropriate starting substances (Table 9).

Tabela 9: Table 9:

2 2

2 2

21 21

Primer A19b Example A19b

Priprema intermedijera 59 Preparation of intermediates 59

[0444] [0444]

[0445] Diizopropil azodikarboksilat (0,221 ml, 1,125 mmol) uz mešanje je ukapavanjem dodat u suspenziju intermedijera 1 (0,27 g, 0,80 mmol), 3-bromhinolin-7-ola (0,18 g, 0,80 mmol) i trifenilfosfinske smole (0,375 g, 3 mmol/g, 1,125 mmol) u THF-u (8 ml) na sobnoj temperaturi. Nakon dodavanja, reakciona smeša je mešana tokom 18 sati. Reakciona smeša je filtrirana kroz sloj Dicalite®. Ostatak je ispran metanolom. Rastvarači iz filtrata su uklonjeni uparavanjem. Ostatak je u datom stanju korišćen u sledećem koraku. [0445] Diisopropyl azodicarboxylate (0.221 ml, 1.125 mmol) was added dropwise to a suspension of intermediate 1 (0.27 g, 0.80 mmol), 3-bromoquinolin-7-ol (0.18 g, 0.80 mmol) and triphenylphosphine resin (0.375 g, 1.125 mmol) in THF with stirring. (8 ml) at room temperature. After the addition, the reaction mixture was stirred for 18 hours. The reaction mixture was filtered through a pad of Dicalite®. The residue was washed with methanol. Solvents from the filtrate were removed by evaporation. The rest was used in the next step as is.

Primer A20 Example A20

Priprema intermedijera 61 Preparation of intermediates 61

[0446] [0446]

[0447] Smeša intermedijera 1 (2,46 g, teorijski 7,54 mmol), 2-metilhinolin-7-ola (1,2 g, 7,54 mmol) i PPh3(5,93 g, 22,6 mmol) u suvom THF-u (40 ml) mešana je na sobnoj temperaturi u atmosferi N2. Ukapavanjem je dodat DIAD (4,57 g, 22,6 mmol). Reakciona smeša je mešana preko noći na sobnoj temperaturi. U smešu je dodata voda (80 ml) i ekstrahovana je pomoću EtOAc (100 ml x 3). Kombinovani organski slojevi su isprani zasićenim vodenim rastvorom soli (100 ml), osušeni iznad anhidrovanog Na2SO4, filtrirani i koncentrovani pod vakuumom. Ostatak je prečišćen hromatografijom na koloni (elucioni gradijent: EtOAc/petrol etar od 1:20 do 1:1). Željene frakcije su sakupljene, i rastvarač je uparen radi dobijanja intermedijera 61 (3,0 g, sirova supstanca). Sirovi intermedijer 61 je korišćen u sledećem koraku reakcije bez daljeg prečišćavanja. [0447] A mixture of intermediate 1 (2.46 g, theoretical 7.54 mmol), 2-methylquinolin-7-ol (1.2 g, 7.54 mmol) and PPh 3 (5.93 g, 22.6 mmol) in dry THF (40 ml) was stirred at room temperature under an atmosphere of N 2 . DIAD (4.57 g, 22.6 mmol) was added dropwise. The reaction mixture was stirred overnight at room temperature. Water (80 mL) was added to the mixture and extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated in vacuo. The residue was purified by column chromatography (elution gradient: EtOAc/petroleum ether from 1:20 to 1:1). The desired fractions were collected, and the solvent was evaporated to give intermediate 61 (3.0 g, crude). The crude intermediate 61 was used in the next reaction step without further purification.

[0448] Sledeći intermedijeri su pripremljeni reakcionim protokolom koji je analogan protokolu korišćenom za pripremu intermedijera 61 koristeći odgovarajuće polazne supstance (Tabela 10). [0448] The following intermediates were prepared by a reaction protocol analogous to the protocol used for the preparation of intermediate 61 using the appropriate starting substances (Table 10).

Tabela 10: Table 10:

21 21

21 21

Primer A21 Example A21

Priprema intermedijera 71 Preparation of intermediates 71

[0449] [0449]

[0450] U rastvor intermedijera 1 (1,00 g, ≈2,92 mmol) i 2-naftola (463 mg, 3,21 mmol) u toluenu (30 ml) dodat je CMBP (1,15 ml, 4,38 mmol). Rastvor je zagrevan na 80°C tokom 18 sati, i zatim je ohlađen na sobnu temperaturu. Reakciona smeša je uparena pod vakuumom. Ostaci su prečišćeni pomoću preparativne LC (nepravilni SiOH 15-40 µm, 120 g Grace, DCM taloženje, gradijent mobilne faze: heptan /EtOAc od 80/20 do 70/30) radi dobijanja intermedijera 71 kao bezbojne gume (1,00 g, prinos 76%). [0450] To a solution of intermediate 1 (1.00 g, ≈2.92 mmol) and 2-naphthol (463 mg, 3.21 mmol) in toluene (30 ml) was added CMBP (1.15 ml, 4.38 mmol). The solution was heated at 80°C for 18 hours, and then cooled to room temperature. The reaction mixture was evaporated under vacuum. The residue was purified by preparative LC (irregular SiOH 15-40 µm, 120 g Grace, DCM precipitation, mobile phase gradient: heptane /EtOAc from 80/20 to 70/30) to afford intermediate 71 as a colorless gum (1.00 g, 76% yield).

Primer A22 Example A22

Priprema intermedijera 72 Preparation of intermediates 72

[0451] [0451]

21 21

[0452] Smeša PPh3(9,07 g, 34,6 mmol) i DEAD (4,82 g, 27,7 mmol) u THF-u (100 ml) mešana je na sobnoj temperaturi tokom 10 min. Zatim je dodat intermedijer 24 (5,0 g, teorijski 13,8 mmol), nakon toga 2-hlorhinolin-7-ol (2,98 g, 16,6 mmol). Dobijena smeša je mešana na sobnoj temperaturi preko noći. Smeša je zatim razblažena sa EtOAc (100 ml), isprana vodom i zasićenim vodenim rastvorom soli. Organska faza je osušena iznad Na2SO4, filtrirana i koncentrovana. Ostatak je prečišćen hromatografijom (elucija: petrol etar/EtOAc = 5/95). Željene frakcije su sakupljene i koncentrovane radi dobijanja intermedijera 72 kao čvrste supstance (6,0 g, prinos 83%). [0452] A mixture of PPh3 (9.07 g, 34.6 mmol) and DEAD (4.82 g, 27.7 mmol) in THF (100 mL) was stirred at room temperature for 10 min. Intermediate 24 (5.0 g, theoretical 13.8 mmol) was then added, followed by 2-chloroquinolin-7-ol (2.98 g, 16.6 mmol). The resulting mixture was stirred at room temperature overnight. The mixture was then diluted with EtOAc (100 mL), washed with water and brine. The organic phase was dried over Na2SO4, filtered and concentrated. The residue was purified by chromatography (elution: petroleum ether/EtOAc = 5/95). The desired fractions were collected and concentrated to give intermediate 72 as a solid (6.0 g, 83% yield).

Primer A23 Example A23

Priprema intermedijera 73 Preparation of intermediates 73

[0453] [0453]

[0454] U rastvor intermedijera 24 (700 mg, teorijski 1,94 mmol) i 4-metilhinolin-7-ola (370 mg, 2,32 mmol) u THF-u (20 ml) dodati su trifenilfosfin (624 mg, 2,71 mmol) i DBAD (711 mg, 2,71 mmol). Smeša je mešana preko noći na sobnoj temperaturi i zatim je uparena pod vakuumom. Sirova supstanca je prečišćena putem preparativne LC (nepravilni SiOH, 15-40 µm, 50 g, Merck, suvo nanošenje (Celite®) gradijent mobilne faze: od 80% heptana, 18% [0454] To a solution of intermediate 24 (700 mg, theoretical 1.94 mmol) and 4-methylquinolin-7-ol (370 mg, 2.32 mmol) in THF (20 ml) was added triphenylphosphine (624 mg, 2.71 mmol) and DBAD (711 mg, 2.71 mmol). The mixture was stirred overnight at room temperature and then evaporated under vacuum. The crude substance was purified by preparative LC (irregular SiOH, 15-40 µm, 50 g, Merck, dry application (Celite®) mobile phase gradient: from 80% heptane, 18%

21 21

EtOAc, 2% MeOH do 10% heptana, 81% EtOAc, 9% MeOH) radi dobijanja intermedijera 73 kao beličaste pene (697 mg, prinos 67%). EtOAc, 2% MeOH to 10% heptane, 81% EtOAc, 9% MeOH) to give intermediate 73 as an off-white foam (697 mg, 67% yield).

[0455] Sledeći intermedijeri su pripremljeni reakcionim protokolom koji je analogan protokolu korišćenom za pripremu intermedijera 73 koristeći odgovarajuće polazne supstance (Tabela 12). [0455] The following intermediates were prepared by a reaction protocol analogous to the protocol used for the preparation of intermediate 73 using the appropriate starting substances (Table 12).

Tabela 12: Table 12:

21 21

Primer A24 Example A24

Priprema intermedijera 77 Preparation of intermediates 77

[0456] [0456]

[0457] Cezijum karbonat (2,18 g, 6,70 mmol) dodat je u rastvor intermedijera 17 (1,15 g, ≈2,23 mmol) i 3-bromhinolin-7-ola (0,5 g, 2,23 mmol) u DMF-u (25 ml). Smeša je mešana preko noći na sobnoj temperaturi. Reakciona smeša je tretirana sa H2O (100 ml) i filtrirana. Dobijeni ostatak je ispran sa H2O (30 ml) i osušen pod sniženim pritiskom radi dobijanja željenog sirovog intermedijera 77 kao bledožute čvrste supstance (1,1 g). [0457] Cesium carbonate (2.18 g, 6.70 mmol) was added to a solution of intermediate 17 (1.15 g, ≈2.23 mmol) and 3-bromoquinolin-7-ol (0.5 g, 2.23 mmol) in DMF (25 mL). The mixture was stirred overnight at room temperature. The reaction mixture was treated with H 2 O (100 mL) and filtered. The resulting residue was washed with H 2 O (30 mL) and dried under reduced pressure to afford the desired crude intermediate 77 as a pale yellow solid (1.1 g).

21 21

[0458] Sledeći intermedijeri su pripremljeni reakcionim protokolom koji je analogan protokolu korišćenom za pripremu intermedijera 77 koristeći odgovarajuće polazne supstance (Tabela 13). [0458] The following intermediates were prepared by a reaction protocol analogous to the protocol used for the preparation of intermediate 77 using the appropriate starting substances (Table 13).

Tabela 13: Table 13:

22 22

Primer A25 Example A25

Priprema intermedijera 79 Preparation of intermediates 79

[0459] [0459]

[0460] U rastvor intermedijera 29 (500 mg, sirov, ≈0,67 mmol) u DMF-u (20 ml) dodati su 3-metoksihinolin-7-ol (187 mg, 0,80 mmol) i Cs2O3(652 mg, 2,0 mmol). Reakciona smeša je mešana na sobnoj temperaturi tokom 12 sati. Smeša je deaktivirana vodom (80 ml) i ekstrahovana DCM-om (50 ml x 3). Organski slojevi su osušeni (Na2SO4), filtrirani, i rastvarač je koncentrovan pod vakuumom radi dobijanja sirovog intermedijera 79 kao žutog ulja (650 mg). [0460] To a solution of intermediate 29 (500 mg, crude, ≈0.67 mmol) in DMF (20 ml) was added 3-methoxyquinolin-7-ol (187 mg, 0.80 mmol) and Cs2O3 (652 mg, 2.0 mmol). The reaction mixture was stirred at room temperature for 12 hours. The mixture was quenched with water (80 mL) and extracted with DCM (50 mL x 3). The organic layers were dried (Na 2 SO 4 ), filtered, and the solvent was concentrated in vacuo to afford crude intermediate 79 as a yellow oil (650 mg).

[0461] Sledeći intermedijeri su pripremljeni reakcionim protokolom koji je analogan protokolu korišćenom za pripremu intermedijera 79 koristeći odgovarajuće polazne supstance (Tabela 14). [0461] The following intermediates were prepared by a reaction protocol analogous to the protocol used for the preparation of intermediate 79 using the appropriate starting substances (Table 14).

Tabela 14: Table 14:

22 22

Primer A26 Example A26

Priprema intermedijera 89 Preparation of intermediates 89

[0462] [0462]

22 22

[0463] Intermedijer 32 (48,3 g, ≈67,99 mmol) rastvoren je u 400 ml DMF-a.7-Br-hinolin-7-ol (16,03 g, ≈67,98 mmol) i Cs2CO3(44,33 g, 135,97 mmol) dodati su u reakcionu smešu, i smeša je mešana na sobnoj temperaturi 16 sati. Reakciona smeša je sipana u 1000 ml hladne vode i ekstrahovana je pomoću EtOAc (2× 600 ml). Organski sloj je ispran vodom (300 ml x 2), osušen anhidrovanim Na2SO4, filtriran, i rastvarač je koncentrovan pod vakuumom radi dobijanja sirovog intermedijera 89 (52 g) kao ulja koje je korišćeno u sledećem koraku bez daljeg prečišćavanja. [0463] Intermediate 32 (48.3 g, ≈67.99 mmol) was dissolved in 400 ml of DMF. 7-Br-quinolin-7-ol (16.03 g, ≈67.98 mmol) and Cs2CO3 (44.33 g, 135.97 mmol) were added to the reaction mixture, and the mixture was stirred at room temperature for 16 hours. The reaction mixture was poured into 1000 mL of cold water and extracted with EtOAc (2×600 mL). The organic layer was washed with water (300 ml x 2), dried over anhydrous Na 2 SO 4 , filtered, and the solvent was concentrated in vacuo to afford crude intermediate 89 (52 g) as an oil which was used in the next step without further purification.

[0464] Sledeći intermedijeri su pripremljeni reakcionim protokolom koji je analogan protokolu korišćenom za pripremu intermedijera 89 koristeći odgovarajuće polazne supstance (Tabela 26 [0464] The following intermediates were prepared by a reaction protocol analogous to the protocol used for the preparation of intermediate 89 using the appropriate starting substances (Table 26

Tabela 26 Table 26

22 22

22 22

22 22

22 22

Primer A27 Example A27

Priprema intermedijera 90 Preparation of intermediate 90

[0465] [0465]

[0466] Smeša intermedijera 15 (893 mg, ≈1,68 mmol), 7-hinolintiola (1,6 g, 3,374 mmol, sirov) i Cs2CO3(1,21 g, 3,72 mmol) u DMF-u (20 ml) mešana je preko noći na sobnoj temperaturi. Reakcija je ugašena vodom (100 ml). Vodena faza je ekstrahovana etil acetatom (200 ml x 2). Kombinovani organski sloj je ispran zasićenim vodenim rastvorom soli (100 ml), osušen iznad Na2SO4i koncentrovan pod sniženim pritiskom. Ostatak je prečišćen na fleš koloni (elucioni gradijent: petrol etar/etil acetat od 100/0 do 1/1) radi dobijanja željenog jedinjenja intermedijera 90 (170 mg, prinos 20%) kao beličaste čvrste supstance. [0466] A mixture of intermediate 15 (893 mg, ≈1.68 mmol), 7-quinolinthiol (1.6 g, 3.374 mmol, crude) and Cs 2 CO 3 (1.21 g, 3.72 mmol) in DMF (20 mL) was stirred overnight at room temperature. The reaction was quenched with water (100 ml). The aqueous phase was extracted with ethyl acetate (200 ml x 2). The combined organic layer was washed with brine (100 mL), dried over Na 2 SO 4 and concentrated under reduced pressure. The residue was purified on a flash column (elution gradient: petroleum ether/ethyl acetate from 100/0 to 1/1) to give the desired compound intermediate 90 (170 mg, yield 20%) as an off-white solid.

2 2

Primer A28 Example A28

Priprema intermedijera 91 Preparation of intermediates 91

[0467] [0467]

[0468] 7-aminohinolin (Ar-NH2u prethodnoj šemi) (700 mg, 4,85 mmol) dodat je u rastvor intermedijera 33 (2,20 g, teorijski 6,80 mmol) u DCM-u (45 ml) i sirćetnoj kiselini (278 µl, 4,85 mmol). Rastvor je mešan tokom 10 min, zatim je dodat triacetoksi borhidrid (2,98 g; 14,1 mmol), i smeša je mešana na sobnoj temperaturi tokom 18 sati. Dodat je zasićeni vodeni rastvor NaHCO3i smeša je mešana tokom 30 minuta. Slojevi su razdvojeni, i vodeni sloj je ekstrahovan DCM-om. Kombinovani organski slojevi su osušeni iznad MgSO4, filtrirani i upareni pod vakuumom. Ostatak je prečišćen pomoću preparativne LC (nepravilni SiOH 15-40 µm, 80 g Grace, gradijent mobilne faze: od 100% DCM do 95% DCM 5%, MeOH) radi dobijanja intermedijera 91 kao žutog ulja koje je kristalisalo tokom stajanja (1,22 g, prinos 56%). [0468] 7-Aminoquinoline (Ar-NH2 in the previous scheme) (700 mg, 4.85 mmol) was added to a solution of intermediate 33 (2.20 g, theoretical 6.80 mmol) in DCM (45 ml) and acetic acid (278 µl, 4.85 mmol). The solution was stirred for 10 min, then triacetoxy borohydride (2.98 g; 14.1 mmol) was added, and the mixture was stirred at room temperature for 18 h. Saturated aqueous NaHCO 3 was added and the mixture was stirred for 30 minutes. The layers were separated, and the aqueous layer was extracted with DCM. The combined organic layers were dried over MgSO4, filtered and evaporated in vacuo. The residue was purified by preparative LC (irregular SiOH 15-40 µm, 80 g Grace, mobile phase gradient: 100% DCM to 95% DCM 5%, MeOH) to afford intermediate 91 as a yellow oil which crystallized on standing (1.22 g, 56% yield).

[0469] Sledeći intermedijeri su pripremljeni reakcionim protokolom koji je analogan protokolu korišćenom za pripremu intermedijera 91 koristeći odgovarajuće polazne supstance (Tabela 15). [0469] The following intermediates were prepared by a reaction protocol analogous to the protocol used for the preparation of intermediate 91 using the appropriate starting substances (Table 15).

Tabela 15: Table 15:

2 1 2 1

Primer A29 Example A29

Priprema intermedijera 96 Preparation of intermediate 96

[0470] [0470]

2 2 2 2

[0471] U rastvor intermedijera 93 (1,0 g, 1,88 mmol) u DMF-u (20 ml) uz mešanje je dodat NaH (60% disperzija u mineralnom ulju) (0,151 g, 3,77 mmol) na 0°C u atmosferi azota. Reakciona smeša je zatim mešana na sobnoj temperaturi tokom 30 minuta. Ukapavanjem je zatim dodat CH3I (0,141 ml, 2,261 mmol). Reakciona smeša je mešana na sobnoj temperaturi tokom 4 sati. Reakciona smeša je deaktivirana sipanjem u laboratorijsku čašu sa ledom i vodom u atmosferi azota. Talog je uklonjen filtracijom, dajući istaloženi int.96. Preostali proizvod je ekstrahovan iz vodenog sloja etil acetatom. Razdvojeni organski sloj je kombinovan sa istaloženim int. 96 i zatim osušen pomoću MgSO4, filtriran, i rastvarači iz filtrata su upareni. Ostatak je rastvoren u etil acetatu i prečišćen na koloni SiO2, tip Grace Reveleris SRC, 40 g, Si 40, na Grace Reveleris X2 sistemu za prečišćavanje koristeći heptan i etil acetat kao eluent sa gradijentom od 100% heptana do 100% etil acetata. Frakcije koje sadrže proizvod su kombinovane i rastvarači su upareni, dajući intermedijer 96 (0,51 g, sirova supstanca). Ovaj intermedijer je korišćen u sledećem reakcionom koraku bez prečišćavanja. [0471] To a solution of intermediate 93 (1.0 g, 1.88 mmol) in DMF (20 ml) was added with stirring NaH (60% dispersion in mineral oil) (0.151 g, 3.77 mmol) at 0°C under a nitrogen atmosphere. The reaction mixture was then stirred at room temperature for 30 minutes. CH3I (0.141 mL, 2.261 mmol) was then added dropwise. The reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was deactivated by pouring it into a beaker with ice and water under a nitrogen atmosphere. The precipitate was removed by filtration, giving precipitated int.96. The remaining product was extracted from the aqueous layer with ethyl acetate. The separated organic layer was combined with the precipitated int. 96 and then dried over MgSO4, filtered, and the solvents from the filtrate were evaporated. The residue was dissolved in ethyl acetate and purified on a SiO2 column, type Grace Reveleris SRC, 40 g, Si 40, on a Grace Reveleris X2 purification system using heptane and ethyl acetate as eluent with a gradient from 100% heptane to 100% ethyl acetate. Fractions containing the product were combined and the solvents were evaporated to give intermediate 96 (0.51 g, crude). This intermediate was used in the next reaction step without purification.

[0472] Sledeći intermedijeri su takođe dobijeni istim reakcionim protokolom koji je korišćen za pripremu intermedijera 96 (Tabela 27). [0472] The following intermediates were also obtained by the same reaction protocol used to prepare intermediate 96 (Table 27).

Tabela 27: Table 27:

2 2

Primer A30 Example A30

Priprema intermedijera 97 Preparation of intermediates 97

[0473] [0473]

[0474] Smeša intermedijera 38 (520 mg, 1,60 mmol), 7-bromhinolina (390 mg, 1,87 mmol) i Et4NCl (261 mg, 1,79 mmol,) u DMF-u (15,00 ml) degasirana je pod vakuumom i tri puta produvana sa N2. U reakcionu smešu su dodati DIEA (1,05 g, 8,15 mmol) i Pd(OAc)2(54,9 mg, 244 µmol). Smeša je mešana na 100°C tokom 16 sati. Smeša je razblažena vodom (20 ml) i ekstrahovana etil acetatom (20 ml x 3). Kombinovana organska faza je osušena anhidrovanim MgSO4, filtrirana i koncentrovana pod vakuumom. Ostatak je prečišćen hromatografijom na silika gelu (ISCO®; 12 g SepaFlash® silika fleš kolona, elucioni gradijent od 100% DCM do 25% etil acetata u DCM-u), dajući intermedijer 97 kao beličastu čvrstu supstancu. (670 mg, prinos 91%; (E)). [0474] A mixture of intermediate 38 (520 mg, 1.60 mmol), 7-bromoquinoline (390 mg, 1.87 mmol) and Et 4 NCl (261 mg, 1.79 mmol) in DMF (15.00 mL) was degassed under vacuum and flushed with N 2 three times. DIEA (1.05 g, 8.15 mmol) and Pd(OAc)2 (54.9 mg, 244 µmol) were added to the reaction mixture. The mixture was stirred at 100°C for 16 hours. The mixture was diluted with water (20 ml) and extracted with ethyl acetate (20 ml x 3). The combined organic phase was dried over anhydrous MgSO4, filtered and concentrated under vacuum. The residue was purified by silica gel chromatography (ISCO®; 12 g SepaFlash® silica flash column, elution gradient from 100% DCM to 25% ethyl acetate in DCM), affording intermediate 97 as an off-white solid. (670 mg, 91% yield; (E)).

[0475] Intermedijeri u tabeli 16 (svi sa E konfiguracijom) pripremljeni su reakcionim protokolom koji je analogan protokolu korišćenom za pripremu intermedijera 97 koristeći odgovarajuće polazne supstance (Tabela 16). [0475] The intermediates in Table 16 (all with the E configuration) were prepared by a reaction protocol analogous to the protocol used to prepare intermediate 97 using the appropriate starting substances (Table 16).

Tabela 16: Table 16:

2 4 2 4

Primer A31 Example A31

Priprema intermedijera 101 Preparation of intermediates 101

[0476] [0476]

[0477] U zaptivenoj epruveti, bis(trifenilfosfin)paladijum(II) dihlorid (79,0 mg; 113 µmol) i bakar(I) jodid (21,4 mg; 113 µmol) dodati su u rastvor 7-bromhininolina (468 mg; 2,25 mmol) [0477] In a sealed tube, bis(triphenylphosphine)palladium(II) dichloride (79.0 mg; 113 µmol) and copper(I) iodide (21.4 mg; 113 µmol) were added to a solution of 7-bromoquinoline (468 mg; 2.25 mmol).

2 2

u 2-metiltetrahidrofuranu (8 ml) koji je prethodno degasiran sa N2. Reakciona smeša je degasirana sa N2i dodat je Et3N (1,25 ml; 9,01 mmol), nakon čega je dodat intermedijer 41 (1,08 g; 3,38 mmol) u (4 ml). Reakciona smeša je degasirana sa N2zatim refluktovana (80°C) tokom 18 h. Nakon hlađenja na sobnu temperaturu, sirova supstanca je raspodeljena na EtOAc i H2O. Vodeni sloj je razdvojen i ekstrahovan pomoću EtOAc. Kombinovani organski slojevi su osušeni iznad MgSO4, filtrirani i upareni pod vakuumom. Ostatak je prečišćen putem preparativne LC (nepravilni SiOH 15-40 µm, 50 g Merck, DCM za nanošenje, gradijent mobilne faze: od 80% heptana, 20% EtOAc do 50% heptana, 50% EtOAc) radi dobijanja intermedijera 101 kao bledožutog ulja (304 mg, prinos: 27%). in 2-methyltetrahydrofuran (8 ml) previously degassed with N2. The reaction mixture was degassed with N 2 and Et 3 N (1.25 mL; 9.01 mmol) was added, followed by the addition of intermediate 41 (1.08 g; 3.38 mmol) in (4 mL). The reaction mixture was degassed with N 2 then refluxed (80°C) for 18 h. After cooling to room temperature, the crude material was partitioned between EtOAc and H2O. The aqueous layer was separated and extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered and evaporated in vacuo. The residue was purified by preparative LC (improper SiOH 15-40 µm, 50 g Merck, DCM application, mobile phase gradient: from 80% heptane, 20% EtOAc to 50% heptane, 50% EtOAc) to afford intermediate 101 as a pale yellow oil (304 mg, yield: 27%).

Primer A32 Example A32

Priprema intermedijera 102 Preparation of intermediates 102

[0478] [0478]

[0479] U rastvor intermedijera 43 (100 mg, 0,323 mmol) i 7-(brom metil)hinolina (117 mg, 0,387 mmol) u DMF-u (3 ml) dodat je NaH (117 mg, 80% čistoće u mineralnom ulju, 1,615 mmol). Smeša je mešana na sobnoj temperaturi tokom 5 h. Reakciona smeša je deaktivirana zasićenim vodenim NH4Cl (10 ml) i ekstrahovana etil acetatom (50 ml x 3). Organska faza je isprana sa H2O (25 ml x 3), osušena anhidrovanim Na2SO4i koncentrovana pod sniženim pritiskom radi dobijanja sirovog proizvoda. Sirovi proizvod je prečišćen pomoću preparativne TLC (petrol etar/etil acetat = 3/2) radi dobijanja intermedijera 102 kao bezbojnog ulja (50 mg, čistoća 91%, prinos 35%). [0479] To a solution of intermediate 43 (100 mg, 0.323 mmol) and 7-(bromomethyl)quinoline (117 mg, 0.387 mmol) in DMF (3 mL) was added NaH (117 mg, 80% purity in mineral oil, 1.615 mmol). The mixture was stirred at room temperature for 5 h. The reaction mixture was quenched with saturated aqueous NH 4 Cl (10 mL) and extracted with ethyl acetate (50 mL x 3). The organic phase was washed with H 2 O (25 ml x 3), dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure to give the crude product. The crude product was purified by preparative TLC (petroleum ether/ethyl acetate = 3/2) to give intermediate 102 as a colorless oil (50 mg, purity 91%, yield 35%).

[0480] Sledeći intermedijeri su pripremljeni reakcionim protokolom koji je analogan protokolu korišćenom za pripremu intermedijera 102 koristeći odgovarajuće polazne supstance (Tabela 17). [0480] The following intermediates were prepared by a reaction protocol analogous to the protocol used for the preparation of intermediate 102 using the appropriate starting substances (Table 17).

2 2

Tabela 17: Table 17:

Primer A33 Example A33

Priprema intermedijera 103 Preparation of intermediates 103

[0481] [0481]

2 2

[0482] Kalijum karbonat (507 mg, 3,67 mmol) dodat je u jednoj porciji u rastvor intermedijera 44 (600 mg, 1,23 mmol) i hinolin-7-ilboronske kiseline (254 mg, 1,47 mmol) u dioksanu (15 ml). Reakciona smeša je mešana na 90°C u atmosferi N2tokom 2 sata, nakon čega je smeša ostavljena da se ohladi na sobnu temperaturu. Nakon toga, dodat je etil acetat, organska faza je isprana zasićenim Na2CO3i zasićenim vodenim rastvorom soli, osušena pomoću MgSO4, filtrirana i koncentrovana pod sniženim pritiskom. Sirovi proizvod je prečišćen hromatografijom na koloni silika gela (elucioni gradijent: heptan/etil acetat od 100/0 do 40/60) radi dobijanja intermedijera 103 (100 mg, prinos 19%). [0482] Potassium carbonate (507 mg, 3.67 mmol) was added in one portion to a solution of intermediate 44 (600 mg, 1.23 mmol) and quinolin-7-ylboronic acid (254 mg, 1.47 mmol) in dioxane (15 mL). The reaction mixture was stirred at 90°C under N2 for 2 hours, after which the mixture was allowed to cool to room temperature. After that, ethyl acetate was added, the organic phase was washed with saturated Na 2 CO 3 and brine, dried over MgSO 4 , filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (elution gradient: heptane/ethyl acetate from 100/0 to 40/60) to give intermediate 103 (100 mg, 19% yield).

[0483] Sledeći intermedijeri su pripremljeni reakcionim protokolom koji je analogan protokolu korišćenom za pripremu intermedijera 103 koristeći odgovarajuće polazne supstance (Tabela 28). [0483] The following intermediates were prepared by a reaction protocol analogous to the protocol used for the preparation of intermediate 103 using the appropriate starting substances (Table 28).

Tabela 28: Table 28:

2 2

Primer A34 Example A34

Priprema intermedijera 104 Preparation of intermediates 104

[0484] [0484]

[0485] Intermedijer 45 (350 mg, sirov, ≈0,626 mmol) rastvoren je u 5 ml dioksana. Dodato je 5 ml NH3.H2O. Smeša je zagrevana u zaptivenoj epruveti (autoklav) na 90°C tokom 12 sati. Smeša je ohlađena na sobnu temperaturu. Rastvarač je koncentrovan pod vakuumom radi dobijanja sirovog intermedijera 104 (300 mg) kao žutog ulja. [0485] Intermediate 45 (350 mg, crude, ≈0.626 mmol) was dissolved in 5 ml of dioxane. 5 ml of NH3.H2O was added. The mixture was heated in a sealed tube (autoclave) at 90°C for 12 hours. The mixture was cooled to room temperature. The solvent was concentrated under vacuum to give crude intermediate 104 (300 mg) as a yellow oil.

Primer A35 Example A35

Priprema intermedijera 105 Preparation of intermediates 105

[0486] [0486]

2 2

[0487] Sirovi intermedijer 59 (dovoljna količina, teorijski 0,83 mmol) rastvoren je u 7 M NH3u MeOH (20 ml, 7 M, 140 mmol). Dobijeni rastvor je mešan i zagrejan na 130°C koristeći mikrotalasno zračenje tokom 2 sata. Rastvarači su upareni. Ostatak je rastvoren u dihlormetanu i prečišćen preko kolone SiO2, tip Grace Reveleris SRC, 12 g, Si 40, na Grace Reveleris X2 sistemu za prečišćavanje koristeći dihlormetan i metanol kao eluent sa gradijentom od 100% DCM za 20 zapremina kolone do 20% MeOH i 80% DCM za 20 zapremina kolone. Frakcije koje sadrže proizvod su kombinovane i rastvarači su upareni, dajući sirovi intermedijer 105 (175 mg) koji je u datom stanju korišćen u sledećem reakcionom koraku. [0487] Crude intermediate 59 (sufficient amount, theoretical 0.83 mmol) was dissolved in 7 M NH 3 in MeOH (20 mL, 7 M, 140 mmol). The resulting solution was stirred and heated to 130°C using microwave radiation for 2 hours. Solvents are evaporated. The residue was dissolved in dichloromethane and purified over a SiO2 column, Grace Reveleris SRC type, 12 g, Si 40, on a Grace Reveleris X2 purification system using dichloromethane and methanol as eluent with a gradient from 100% DCM for 20 column volumes to 20% MeOH and 80% DCM for 20 column volumes. Fractions containing the product were combined and the solvents were evaporated, yielding crude intermediate 105 (175 mg) which was used as is in the next reaction step.

[0488] Intermedijeri u tabeli 18 su pripremljeni analognim reakcionim protokolom koji je opisan u A34 ili A35 koristeći odgovarajuće polazne supstance (Tabela 18). Intermedijeri 136, 137 i 138 su dobijeni u E konfiguraciji. [0488] The intermediates in Table 18 were prepared by an analogous reaction protocol to that described in A34 or A35 using the appropriate starting substances (Table 18). Intermediates 136, 137 and 138 were obtained in the E configuration.

Tabela 18 Table 18

24 24

Int. struktura Ref Polazne supstance Int. structure Ref Starting substances

Int. struktura Ref Polazne supstance Int. structure Ref Starting substances

Int. struktura Ref Polazne supstance Int. structure Ref Starting substances

24 24

Int. struktura Ref Polazne supstance Int. structure Ref Starting substances

Int. struktura Ref Polazne supstance Int. structure Ref Starting substances

24 24

Int. struktura Ref Polazne supstance Int. structure Ref Starting substances

24 24

Int. struktura Ref Polazne supstance Int. structure Ref Starting substances

24 24

Int. struktura Ref Polazne supstance Int. structure Ref Starting substances

24 24

Int. struktura Ref Polazne supstance Int. structure Ref Starting substances

24 24

Int. struktura Ref Polazne supstance Int. structure Ref Starting substances

2 2

Int. struktura Ref Polazne supstance Int. structure Ref Starting substances

21 21

Int. struktura Ref Polazne supstance Int. structure Ref Starting substances

22 22

Primer A36 Example A36

Priprema intermedijera 144 i 144a [0489] Preparation of Intermediates 144 and 144a [0489]

2 2

[0490] Rastvor intermedijera 56 (35,7 mg, ≈0,0662 mmol) u 7 M NH3u MeOH (1 ml, 7 mmol) mešan je i zagrevan na 130°C koristeći mikrotalasno zračenje tokom 1 sata. Rastvarači su upareni. Ostatak je prečišćen pomoću prep. HPLC (stacionarna faza: RP XBridge Prep C18 OBD-10 µm, 30 x 150 mm, mobilna faza: 0,25% NH4HCO3rastvor u vodi, CH3CN). Rastvarači iz prečišćenih frakcija su upareni, i zajedno upareni sa MeOH, dajući intermedijer 144 (12,9 mg, prinos 37%) i intermedijer 144a (26,5 mg, 73%). [0490] A solution of intermediate 56 (35.7 mg, ≈0.0662 mmol) in 7 M NH3 in MeOH (1 ml, 7 mmol) was stirred and heated to 130°C using microwave irradiation for 1 hour. Solvents are evaporated. The residue was purified using prep. HPLC (stationary phase: RP XBridge Prep C18 OBD-10 µm, 30 x 150 mm, mobile phase: 0.25% NH4HCO3 aqueous solution, CH3CN). The solvents from the purified fractions were evaporated, and coevaporated with MeOH, to give intermediate 144 (12.9 mg, 37% yield) and intermediate 144a (26.5 mg, 73%).

Primer A37 Example A37

Priprema intermedijera 145 i 145a Preparation of intermediates 145 and 145a

[0491] [0491]

2 4 2 4

Rastvor sirovog intermedijera 57 (teorijski 2,36 mmol) u 7 M NH3u MeOH (20 ml, 7 mmol) mešan je i zagrevan na 130°C koristeći mikrotalasno zračenje tokom 2 sata. Rastvarači su upareni. Ostatak je rastvoren u DCM-u sa MeOH i prečišćen preko kolone SiO2, type Grace Reveleris SRC, 40 g, Si 40, na Armen Spot II Ultimate sistemu za prečišćavanje (elucioni gradijent: DCM:MeOH od 100:0 do 20:80). Frakcije koje sadrže proizvod su kombinovane i rastvarači su uklonjeni, dajući sirovi intermedijer 145 (0,64 g) i sirovi intermedijer 145a (0,13 g). Oba sirova intermedijera su korišćena u sledećem koraku reakcije bez daljeg prečišćavanja. A solution of crude intermediate 57 (theoretical 2.36 mmol) in 7 M NH 3 in MeOH (20 mL, 7 mmol) was stirred and heated at 130 °C using microwave irradiation for 2 h. Solvents are evaporated. The residue was dissolved in DCM with MeOH and purified over a SiO2 column, type Grace Reveleris SRC, 40 g, Si 40, on an Armen Spot II Ultimate purification system (elution gradient: DCM:MeOH from 100:0 to 20:80). Fractions containing the product were combined and the solvents were removed, yielding crude intermediate 145 (0.64 g) and crude intermediate 145a (0.13 g). Both crude intermediates were used in the next reaction step without further purification.

Primer A38 Example A38

Priprema intermedijera 146 Preparation of intermediates 146

[0492] [0492]

[0493] U smešu intermedijera 137 (340 mg, teorijski 795 µmol) u MeOH (10,0 ml) dodat je Pd/C (100 mg, 10%) na 25°C. Suspenzija je degasirana pod vakuumom i produvana sa H2(nekoliko puta). Smeša je mešana u atmosferi H2(15 psi) na 25°C tokom 5 sati. Smeša je [0493] To a mixture of intermediate 137 (340 mg, theoretical 795 µmol) in MeOH (10.0 mL) was added Pd/C (100 mg, 10%) at 25°C. The suspension was degassed under vacuum and purged with H2 (several times). The mixture was stirred under H 2 (15 psi) at 25°C for 5 hours. It's confusing

2 2

filtrirana i filtrat je koncentrovan. Ostatak je prečišćen pomoću preparativne HPLC (kolona: Diamonsil 150*20 mm, 5 µm, mobilna faza: od 15% MeCN u vodi (0,225% mravlja kiselina) do 45% MeCN u vodi (0,225% mravlja kiselina) filtered and the filtrate was concentrated. The residue was purified by preparative HPLC (column: Diamonsil 150*20 mm, 5 µm, mobile phase: from 15% MeCN in water (0.225% formic acid) to 45% MeCN in water (0.225% formic acid)

[0494] Protok (ml/min): 25 ml/min). Frakcije koje sadrže željeni proizvod su kombinovane i liofilizovane. Ostatak je dalje prečišćen pomoću hiralne SFC (kolona: OD (250 mm*30 mm,10 µm), mobilna faza: superkritična CO2/ EtOH NH3.H2O (0,1%) = 50/50 protok: 80 ml/min). [0494] Flow (ml/min): 25 ml/min). Fractions containing the desired product were combined and lyophilized. The residue was further purified by chiral SFC (column: OD (250 mm*30 mm,10 µm), mobile phase: supercritical CO2/EtOH NH3.H2O (0.1%) = 50/50 flow: 80 ml/min).

Intermedijer 146 (130 mg, prinos 38%) dobijen je kao bela čvrsta supstanca. Intermediate 146 (130 mg, 38% yield) was obtained as a white solid.

[0495] Sledeći intermedijeri su pripremljeni reakcionim protokolom koji je analogan protokolu koji je opisan za pripremu intermedijera 146 koristeći odgovarajuće polazne supstance (Tabela 19). [0495] The following intermediates were prepared by a reaction protocol analogous to the protocol described for the preparation of intermediate 146 using the appropriate starting substances (Table 19).

Tabela 19: Table 19:

Primer A39 Example A39

Priprema intermedijera 149 Preparation of intermediates 149

[0496] [0496]

2 2

[0497] U rastvor intermedijera 70 (360 mg, ≈542 µmol) u THF-u (3,00 ml) dodat je iPrOH (3,00 ml) i amonijak (28% u vodi, 6,00 ml). Smeša je mešana na 85°C tokom 72 sata u autoklavu. Rastvarač je uklonjen i ostatak je prečišćen fleš hromatografijom na koloni silika gela (elucioni gradijent: MeOH/DCM od 0/100 do 4/96), dajući intermedijer 149 kao belu čvrstu supstancu. (230 mg, prinos 65%). [0497] To a solution of intermediate 70 (360 mg, ≈542 µmol) in THF (3.00 mL) was added iPrOH (3.00 mL) and ammonia (28% in water, 6.00 mL). The mixture was stirred at 85°C for 72 hours in an autoclave. The solvent was removed and the residue was purified by flash column chromatography on silica gel (elution gradient: MeOH/DCM from 0/100 to 4/96) to give intermediate 149 as a white solid. (230 mg, yield 65%).

[0498] Intermedijer u tabeli 20 je pripremljen reakcionim protokolom koji je analogan protokolu korišćenom za pripremu intermedijera 149 koristeći odgovarajuće polazne supstance (Tabela 20). Intermedijer 150 je dobijen u E konfiguraciji. [0498] The intermediate in Table 20 was prepared by a reaction protocol that is analogous to the protocol used to prepare intermediate 149 using the appropriate starting substances (Table 20). Intermediate 150 was obtained in the E configuration.

Tabela 20: Table 20:

Primer A40 Example A40

Priprema intermedijera 151 Preparation of intermediates 151

[0499] [0499]

2 2

[0500] Suspenzija intermedijera 150 (150 mg, 349 µmol) i Pd/C (80 mg, 10%) mešana je u atmosferi H2(15 psi) tokom 7 sati na 15°C. Reakciona smeša je filtrirana kroz celit. Filtrat je koncentrovan pod sniženim pritiskom radi dobijanja intermedijera 151 kao žute čvrste supstance (135 mg, prinos 90%). [0500] A suspension of intermediate 150 (150 mg, 349 µmol) and Pd/C (80 mg, 10%) was stirred under H2 (15 psi) for 7 hours at 15°C. The reaction mixture was filtered through celite. The filtrate was concentrated under reduced pressure to afford intermediate 151 as a yellow solid (135 mg, 90% yield).

Primer A41 Example A41

Priprema intermedijera 152 Preparation of intermediates 152

[0501] [0501]

[0502] U rastvor intermedijera 119 (550 mg, teorijski 1,18 mmol) u DMA (20 ml) dodati su cink cijanid (410 mg, 3,49 mmol), cink (55 mg, 0,86 mmol), Tris(dibenzilidenaceton)dipaladijum (46 mg, 0,051 mmol), 1,1'-bis(difenilfosfino)ferocen (92 mg, 0,17 mmol). Smeša je mešana na 100°C tokom 12 sati u atmosferi N2. Katalizator je filtriran i rastvarač je uparen. Ostatak je prečišćen fleš hromatografijom na koloni silika gela (elucioni gradijent: EtOAc/petrol etar od 1/20 do 1/0). Rastvarač je uparen radi dobijanja intermedijera 152 kao ulja (450 mg, prinos 70%). [0502] To a solution of intermediate 119 (550 mg, theoretical 1.18 mmol) in DMA (20 ml) were added zinc cyanide (410 mg, 3.49 mmol), zinc (55 mg, 0.86 mmol), Tris(dibenzylideneacetone)dipalladium (46 mg, 0.051 mmol), 1,1'-bis(diphenylphosphino)ferrocene (92 mg, 0.17 mmol). The mixture was stirred at 100°C for 12 hours under N2 atmosphere. The catalyst was filtered and the solvent was evaporated. The residue was purified by flash chromatography on a silica gel column (elution gradient: EtOAc/petroleum ether from 1/20 to 1/0). The solvent was evaporated to give intermediate 152 as an oil (450 mg, 70% yield).

Primer A56 Example A56

Priprema intermedijera 214 Preparation of intermediates 214

2 2

[0504] Smeša intermedijera 105 (512 mg, 1 mmol), CuCN (358,2 mg, 4 mmol), Pd2dba3(92 mg, 0,1 mmol) i DPPF (221,7 mg, 0,4 mmol) u dioksanu (6 ml) mešana je na 100°C tokom 16 h. Reakciona smeša je ohlađena, sipana u vodu i tri puta ekstrahovana etil acetatom. Organski sloj je dva puta ispran vodom. Organski sloj je osušen i uparen do suva. Ostatak je prečišćen pomoću prep. HPLC (stacionarna faza: RP XBridge Prep C18 OBD-10 µm, 50x150 mm, mobilna faza: 0,25% NH4HCO3rastvor u vodi, CH3CN), dajući intermedijer 214 (363 mg, prinos 79%). [0504] A mixture of intermediate 105 (512 mg, 1 mmol), CuCN (358.2 mg, 4 mmol), Pd2dba3 (92 mg, 0.1 mmol) and DPPF (221.7 mg, 0.4 mmol) in dioxane (6 mL) was stirred at 100°C for 16 h. The reaction mixture was cooled, poured into water and extracted three times with ethyl acetate. The organic layer was washed twice with water. The organic layer was dried and evaporated to dryness. The residue was purified using prep. HPLC (stationary phase: RP XBridge Prep C18 OBD-10 µm, 50x150 mm, mobile phase: 0.25% NH4HCO3 aqueous solution, CH3CN), affording intermediate 214 (363 mg, 79% yield).

Primer A42 Example A42

Priprema intermedijera 153 Preparation of intermediates 153

[0505] [0505]

[0506] Smeša intermedijera 23 (50 mg, teorijski 0,13 mmol), 7-hidroksihinolina (22 mg, 0,156 mmol) i PPh3(53 mg, 0,26 mmol) u suvom THF-u (20 ml) mešana je na sobnoj temperaturi u atmosferi N2. Ukapavanjem je dodat DIAD (6,47 g, 32,037 mmol). Reakciona smeša je mešana na sobnoj temperaturi tokom 2 sata. Reakciona smeša je uparena do suva, dajući sirovi intermedijer 153. [0506] A mixture of intermediate 23 (50 mg, theoretical 0.13 mmol), 7-hydroxyquinoline (22 mg, 0.156 mmol) and PPh 3 (53 mg, 0.26 mmol) in dry THF (20 ml) was stirred at room temperature under an atmosphere of N 2 . DIAD (6.47 g, 32.037 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was evaporated to dryness, affording crude intermediate 153.

2 2

Primer A43 Example A43

Priprema intermedijera 154 i intermedijera 154a Preparation of intermediate 154 and intermediate 154a

[0507] [0507]

[0508] U rastvor intermedijera 72 (1,0 g, 1,91 mmol) u 1,4-dioksanu (10 ml) dodat je 2 M NaOH (10 ml, 20 mmol). Reakciona smeša je mešana na 150°C tokom 1 sata u mikrotalasnoj pećnici. Smeša je razblažena vodom (15 ml), ekstrahovana pomoću EtOAc (10 ml x 3). Organska faza je isprana zasićenim vodenim rastvorom soli (15 ml), osušena iznad Na2SO4, filtrirana i koncentrovana. Ostatak je prečišćen hromatografijom na koloni (elucija: EtOAc/MeOH 85/15). Željene frakcije su sakupljene i koncentrovane radi dobijanja intermedijera 154 (359 mg bele čvrste supstance, prinos 41%) i intermedijera 154a (300 mg, prinos 32%). [0508] To a solution of intermediate 72 (1.0 g, 1.91 mmol) in 1,4-dioxane (10 mL) was added 2 M NaOH (10 mL, 20 mmol). The reaction mixture was stirred at 150°C for 1 hour in a microwave oven. The mixture was diluted with water (15 mL), extracted with EtOAc (10 mL x 3). The organic phase was washed with brine (15 mL), dried over Na 2 SO 4 , filtered and concentrated. The residue was purified by column chromatography (elution: EtOAc/MeOH 85/15). The desired fractions were collected and concentrated to give intermediate 154 (359 mg white solid, 41% yield) and intermediate 154a (300 mg, 32% yield).

Primer A44 Example A44

Priprema intermedijera 155 Preparation of intermediates 155

[0509] [0509]

2 2

[0510] Natrijum (440 mg, 19,1 mmol) mešan je u MeOH (25 ml) na sobnoj temperaturi dok se nije potpuno rastvorio. Intermedijer 72 (1,0 g, 1,91 mmol) nakon toga je dodat u reakcionu smešu, i reakciona smeša je refluktovana tokom 72 sata. Smeša je razblažena DCM-om (100 ml), isprana vodom (10 ml), zasićenim vodenim rastvorom soli (10 ml). Organska faza je osušena iznad Na2SO4, filtrirana i koncentrovana radi dobijanja sirovog intermedijera 155 koji je u datom stanju korišćen u sledećem reakcionom koraku bez daljeg prečišćavanja. [0510] Sodium (440 mg, 19.1 mmol) was stirred in MeOH (25 mL) at room temperature until completely dissolved. Intermediate 72 (1.0 g, 1.91 mmol) was then added to the reaction mixture, and the reaction mixture was refluxed for 72 hours. The mixture was diluted with DCM (100 mL), washed with water (10 mL), brine (10 mL). The organic phase was dried over Na 2 SO 4 , filtered and concentrated to give crude intermediate 155 which was used as is in the next reaction step without further purification.

Primer A45 Example A45

Priprema intermedijera 157 Preparation of intermediates 157

[0511] [0511]

[0512] 7-brom-2-hlor-hinolin (10,0 g, 41,2 mmol) i ciklopropil metilamin (18 ml) u EtOH (80 ml) mešani su u zaptivenoj epruveti na 120°C preko noći. Smeša je uparena pod vakuumom radi dobijanja intermedijera 157 (15 g; sirov) kao smeđe čvrste supstance koja je u datom stanju korišćena u sledećem koraku reakcije bez daljeg prečišćavanja. [0512] 7-Bromo-2-chloro-quinoline (10.0 g, 41.2 mmol) and cyclopropyl methylamine (18 mL) in EtOH (80 mL) were stirred in a sealed tube at 120 °C overnight. The mixture was evaporated under vacuum to give intermediate 157 (15 g; crude) as a brown solid which was used as is in the next step of the reaction without further purification.

Priprema intermedijera 159 Preparation of intermediates 159

[0513] [0513]

2 1 2 1

[0514] Intermedijer 38 (3,8 g, 11,9 mmol) u 9-BBN (0,5 M u THF-u, 95,1 ml, 47,5 mmol) refluktovan je tokom 1 h u atmosferi N2. Smeša je ohlađena na sobnu temperaturu, zatim je dodat K3PO4(7,56 g, 35,6 mmol) u H2O (20 ml) pa onda THF (150 ml), intermedijer 157 (4,4 g, ≈13 mmol) i Pd-118 (155 mg, 0,24 mmol). Dobijena smeša je refluktovana preko noći. Smeša je razblažena sa H2O (100 ml), ekstrahovana etil acetatom (150 ml), organska faza je osušena pomoću Na2SO4, zatim filtrirana i koncentrovana pod vakuumom radi dobijanja sirovog proizvoda. Sirovi proizvod je prečišćen hromatografijom (etil acetat/petrol etar 0/1 do 1/3) radi dobijanja intermedijera 159 (3,1 g, prinos: 42,8%) kao žutog ulja. [0514] Intermediate 38 (3.8 g, 11.9 mmol) in 9-BBN (0.5 M in THF, 95.1 ml, 47.5 mmol) was refluxed for 1 h under N 2 . The mixture was cooled to room temperature, then K3PO4 (7.56 g, 35.6 mmol) in H2O (20 mL) and then THF (150 mL), intermediate 157 (4.4 g, ≈13 mmol) and Pd-118 (155 mg, 0.24 mmol) were added. The resulting mixture was refluxed overnight. The mixture was diluted with H 2 O (100 ml), extracted with ethyl acetate (150 ml), the organic phase was dried over Na 2 SO 4 , then filtered and concentrated in vacuo to give the crude product. The crude product was purified by chromatography (ethyl acetate/petroleum ether 0/1 to 1/3) to give intermediate 159 (3.1 g, yield: 42.8%) as a yellow oil.

[0515] Sledeći intermedijeri su pripremljeni reakcionim protokolom koji je analogan protokolu korišćenom za pripremu intermedijera 159 koristeći odgovarajuće polazne supstance (Tabela 29). [0515] The following intermediates were prepared by a reaction protocol analogous to the protocol used for the preparation of intermediate 159 using the appropriate starting substances (Table 29).

Tabela 29: Table 29:

2 2 2 2

2 Int. Struktura Polazne supstance 2 Int. Structure of the starting substance

24 24

2 2

2 2

2 2

2 2

Priprema intermedijera 160 Preparation of intermediates 160

[0516] [0516]

[0517] Reakcija je obavljena u zaptivenoj epruveti. Intermedijer 159 (3,1 g, ≈5,1 mmol) dodat je u NH3.H2O (30 ml) i dioksan (30 ml) i mešan je na 120°C preko noći. Smeša je koncentrovana pod vakuumom radi dobijanja sirovog intermedijera 160. Ostatak je prečišćen hromatografijom na silika gelu (etil acetat 100% do etil acetat/MeOH 90/10) radi dobijanja intermedijera 160 (3,95 g, prinos: 77%). [0517] The reaction was carried out in a sealed tube. Intermediate 159 (3.1 g, ≈5.1 mmol) was added to NH 3 .H 2 O (30 mL) and dioxane (30 mL) and stirred at 120 °C overnight. The mixture was concentrated under vacuum to give crude intermediate 160. The residue was purified by silica gel chromatography (ethyl acetate 100% to ethyl acetate/MeOH 90/10) to give intermediate 160 (3.95 g, yield: 77%).

Primer A46 Example A46

Priprema intermedijera 161 Preparation of intermediates 161

[0518] [0518]

2 2

[0519] 7-brom-2-hlor-hinolin (1,5 g, 6,18 mmol) i 2,2-difluoretilamin (0,552 g, 6,804 mmol) u EtOH (30 ml) zagrevani su u zaptivenoj epruveti na 120°C preko noći. Smeša je uparena pod vakuumom radi dobijanja intermedijera 161 (1,8 g, prinos: 88,1%) kao smeđe čvrste supstance koja je korišćena u sledećem koraku bez daljeg prečišćavanja. [0519] 7-Bromo-2-chloro-quinoline (1.5 g, 6.18 mmol) and 2,2-difluoroethylamine (0.552 g, 6.804 mmol) in EtOH (30 mL) were heated in a sealed tube at 120°C overnight. The mixture was evaporated under vacuum to give intermediate 161 (1.8 g, yield: 88.1%) as a brown solid which was used in the next step without further purification.

Priprema intermedijera 162 Preparation of intermediates 162

[0520] [0520]

[0521] Intermedijer 38 (500 mg, 1,56 mmol) u 9-BBN (0,5 M u THF-u, 15,6 ml, 7,8 mmol) refluktovan je tokom 1 h u atmosferi N2. Smeša je ohlađena na sobnu temperaturu, zatim je dodat K3PO4(995,6 mg, 4,7 mmol) u H2O (2 ml) pa onda THF (20 ml), intermedijer 161 (538,7 mg, ≈1,88 mmol) i Pd-118 (20,4 mg, 0,031 mmol). Dobijena smeša je refluktovana preko noći. Smeša je razblažena dodatkom H2O (60 ml), ekstrahovana etil acetatom (100 ml x2), kombinovane organske faze su osušene sa Na2SO4, zatim filtrirane i koncentrovane pod vakuumom radi dobijanja sirovog proizvoda. Sirovi proizvod je prečišćen hromatografijom (etil acetat: petrol etar odnos 1:10 do 1:5) radi dobijanja intermedijera 162 (650 mg, prinos: 68,1%) kao žutog ulja. [0521] Intermediate 38 (500 mg, 1.56 mmol) in 9-BBN (0.5 M in THF, 15.6 mL, 7.8 mmol) was refluxed for 1 h under N 2 . The mixture was cooled to room temperature, then K3PO4 (995.6 mg, 4.7 mmol) in H2O (2 mL) and then THF (20 mL), intermediate 161 (538.7 mg, ≈1.88 mmol) and Pd-118 (20.4 mg, 0.031 mmol) were added. The resulting mixture was refluxed overnight. The mixture was diluted with H 2 O (60 ml), extracted with ethyl acetate (100 ml x 2), the combined organic phases were dried with Na 2 SO 4 , then filtered and concentrated in vacuo to give the crude product. The crude product was purified by chromatography (ethyl acetate:petroleum ether ratio 1:10 to 1:5) to give intermediate 162 (650 mg, yield: 68.1%) as a yellow oil.

Priprema intermedijera 163 Preparation of intermediates 163

[0522] [0522]

2 2

[0523] Reakcija je obavljena u zaptivenoj epruveti. Intermedijer 162 (650 mg, ≈1,06 mmol) dodat je u NH3.H2O (15 ml) i dioksan (10 ml) i mešan je na 120°C preko noći. Smeša je koncentrovana pod vakuumom radi dobijanja intermedijera 163 (680 mg, prinos: 97,9%). [0523] The reaction was carried out in a sealed tube. Intermediate 162 (650 mg, ≈1.06 mmol) was added to NH 3 .H 2 O (15 mL) and dioxane (10 mL) and stirred at 120 °C overnight. The mixture was concentrated under vacuum to give intermediate 163 (680 mg, yield: 97.9%).

Primer A47 Example A47

Priprema intermedijera 164 Preparation of intermediates 164

[0524] [0524]

[0525] Smeša 7-brom-2-hlorhinolina (10 g, 41,24 mmol) i 4-metoksibenzilamina (11,3 g, 82,5 mmol) u etanolu (40 ml) zagrejana je u zaptivenoj epruveti na 120°C tokom 72 h. Smeša je uparena pod sniženim pritiskom i prečišćena hromatografijom na koloni (elucioni gradijent: CH2Cl2/petrol etar od 1/10 do 1/0) radi dobijanja željenog proizvoda intermedijera 164 (13 g, prinos 82%) kao bele čvrste supstance. [0525] A mixture of 7-bromo-2-chloroquinoline (10 g, 41.24 mmol) and 4-methoxybenzylamine (11.3 g, 82.5 mmol) in ethanol (40 ml) was heated in a sealed tube at 120°C for 72 h. The mixture was evaporated under reduced pressure and purified by column chromatography (elution gradient: CH 2 Cl 2 /petroleum ether from 1/10 to 1/0) to give the desired product intermediate 164 (13 g, 82% yield) as a white solid.

Priprema intermedijera 165 Preparation of intermediates 165

[0526] [0526]

[0527] Smeša intermedijera 38 (2 g, 5,0 mmol) u 9-BBN (50,0 ml, 25,0 mmol, 0,5 M u THF-u) refluktovana je tokom 1 h u atmosferi N2. Smeša je ohlađena na sobnu temperaturu, zatim je dodat K3PO4(3,18 mg, 15,0 mmol) u H2O (10 ml), pa onda THF (20 ml), intermedijer 164 [0527] A mixture of intermediate 38 (2 g, 5.0 mmol) in 9-BBN (50.0 ml, 25.0 mmol, 0.5 M in THF) was refluxed for 1 h under N 2 . The mixture was cooled to room temperature, then K3PO4 (3.18 mg, 15.0 mmol) in H2O (10 mL) was added, followed by THF (20 mL), intermediate 164

2 1 2 1

(2,58 mg, ≈7,50 mmol) i [1,1'-bis(difenilfosfino)ferocen]dihlorpaladijum(II) (163,0 mg, 0,25 mmol). Dobijena smeša je refluktovana tokom 3 h. Smeša je koncentrovana. Ostatak je rastvoren u etil acetatu (40 ml), ispran vodom (6 ml), zasićenim vodenim rastvorom soli (6 ml). Organska faza je osušena iznad Na2SO4, filtrirana i koncentrovana radi dobijanja sirovog proizvoda. On je prečišćen hromatografijom na koloni (elucioni gradijent: etil acetat/petrol etar od 1/10 do 1/1). Željene frakcije su sakupljene i koncentrovane radi dobijanja proizvoda intermedijera 165 kao čvrste supstance (2 g, prinos 52,4%). (2.58 mg, ≈7.50 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (163.0 mg, 0.25 mmol). The resulting mixture was refluxed for 3 h. The mixture is concentrated. The residue was dissolved in ethyl acetate (40 ml), washed with water (6 ml), saturated aqueous salt solution (6 ml). The organic phase was dried over Na2SO4, filtered and concentrated to give the crude product. It was purified by column chromatography (elution gradient: ethyl acetate/petroleum ether from 1/10 to 1/1). The desired fractions were collected and concentrated to give the product intermediate 165 as a solid (2 g, 52.4% yield).

[0528] Sledeći intermedijeri su pripremljeni reakcionim protokolom koji je analogan protokolu korišćenom za pripremu intermedijera 165 koristeći odgovarajuće polazne supstance (Tabela 30). [0528] The following intermediates were prepared by a reaction protocol analogous to the protocol used to prepare intermediate 165 using the appropriate starting substances (Table 30).

Tabela 30: Table 30:

2 2 2 2

Priprema intermedijera 166 Preparation of intermediates 166

2 2

[0530] Smeša intermedijera 165 (500 mg, ≈0,655 mmol) i NH3.H2O (10 ml) u dioksanu (10 ml) zagrevana je u zaptivenoj epruveti na 120°C tokom 14 h. Ova reakcija je uparena pod vakuumom radi dobijanja intermedijera 166 (400 mg, prinos 93,5%) kao ulja. [0530] A mixture of intermediate 165 (500 mg, ≈0.655 mmol) and NH 3 .H 2 O (10 ml) in dioxane (10 ml) was heated in a sealed tube at 120 °C for 14 h. This reaction was evaporated under vacuum to give intermediate 166 (400 mg, 93.5% yield) as an oil.

Priprema intermedijera 167 Preparation of intermediates 167

[0531] [0531]

[0532] Smeša intermedijera 166 (340 mg, ≈0,52 mmol) u CF3COOH (5 ml) mešana je na 60°C tokom 1 h. Smeša je uparena pod vakuumom radi dobijanja intermedijera 167 kao sirovog proizvoda (300 mg, prinos 85,9%). [0532] A mixture of intermediate 166 (340 mg, ≈0.52 mmol) in CF 3 COOH (5 mL) was stirred at 60 °C for 1 h. The mixture was evaporated under vacuum to give intermediate 167 as crude product (300 mg, 85.9% yield).

Primer A48 Example A48

Priprema intermedijera 168 Preparation of intermediates 168

[0533] [0533]

2 4 2 4

[0534] Intermedijer 165 (300 mg, ≈0,39 mmol) rastvoren je u EtOH (20 ml) i etil acetatu (4 ml) i hidrogenovan je pod 1 atm H2iznad Pd(OH)2/C (30 mg) tokom 7 sati. Smeša je filtrirana i uparena pod vakuumom radi dobijanja intermedijera 168 kao sirovog proizvoda (200 mg, prinos 70,6%). [0534] Intermediate 165 (300 mg, ≈0.39 mmol) was dissolved in EtOH (20 mL) and ethyl acetate (4 mL) and hydrogenated under 1 atm H 2 over Pd(OH) 2 /C (30 mg) for 7 hours. The mixture was filtered and evaporated under vacuum to give intermediate 168 as crude product (200 mg, 70.6% yield).

Priprema intermedijera 169 Preparation of intermediates 169

[0535] [0535]

[0536] Smeša intermedijera 168 (200 mg, ≈0,278 mmol) u CF3COOH (5 ml) mešana je na 60°C tokom 1 h. Smeša je uparena pod vakuumom radi dobijanja intermedijera 169 kao sirovog proizvoda (120 mg, prinos 89,0%). [0536] A mixture of intermediate 168 (200 mg, ≈0.278 mmol) in CF 3 COOH (5 mL) was stirred at 60 °C for 1 h. The mixture was evaporated under vacuum to give intermediate 169 as crude product (120 mg, 89.0% yield).

Primer A49 Example A49

Priprema intermedijera 170 Preparation of intermediates 170

[0537] [0537]

2 2

[0538] Smeša intermedijera 165 (310 mg, ≈0,406 mmol) i CH3NH2/H2O (5 ml) u dioksanu (5 ml) mešana je u zaptivenoj epruveti na 120°C tokom 14 h. Ova smeša je uparena pod vakuumom radi dobijanja intermedijera 170 (200 mg, prinos 80,1%) kao sirovog proizvoda. [0538] A mixture of intermediate 165 (310 mg, ≈0.406 mmol) and CH 3 NH 2 /H 2 O (5 ml) in dioxane (5 ml) was stirred in a sealed tube at 120 °C for 14 h. This mixture was evaporated under vacuum to give intermediate 170 (200 mg, 80.1% yield) as crude product.

Priprema intermedijera 171 Preparation of intermediates 171

[0539] [0539]

[0540] Smeša intermedijera 170 (200 mg, ≈0,325 mmol) u CF3COOH (5 ml) mešana je na 50°C tokom 1 h. Smeša je uparena pod vakuumom radi dobijanja intermedijera 171 (160 mg, prinos 84,0%) kao sirovog proizvoda. [0540] A mixture of intermediate 170 (200 mg, ≈0.325 mmol) in CF 3 COOH (5 ml) was stirred at 50 °C for 1 h. The mixture was evaporated under vacuum to give intermediate 171 (160 mg, yield 84.0%) as crude product.

Primer A50 Example A50

Priprema intermedijera 172 Preparation of intermediates 172

[0541] [0541]

2 2

[0542] Smeša intermedijera 165 (300 mg, 0,393 mmol) i natrijum metoksida (63,7 mg, 1,18 mmol) u metanolu (10 ml) refluktovana je na 60°C tokom 12 h. Smeša je uparena pod vakuumom radi dobijanja sirovog proizvoda. Dodata je voda (10 ml), smeša je ekstrahovana etil acetatom (10 ml x 2), organski slojevi su kombinovani i upareni pod vakuumom radi dobijanja intermedijera 172 (200 mg, prinos 71,8%) kao sirovog proizvoda. [0542] A mixture of intermediate 165 (300 mg, 0.393 mmol) and sodium methoxide (63.7 mg, 1.18 mmol) in methanol (10 mL) was refluxed at 60 °C for 12 h. The mixture was evaporated under vacuum to give the crude product. Water (10 mL) was added, the mixture was extracted with ethyl acetate (10 mL x 2), the organic layers were combined and evaporated in vacuo to afford intermediate 172 (200 mg, 71.8% yield) as crude product.

Priprema intermedijera 173 Preparation of intermediates 173

[0543] [0543]

[0544] Smeša intermedijera 172 (200 mg, ≈0,282 mmol) u TFA (5 ml) mešana je na 60°C tokom 1 h. Smeša je uparena pod vakuumom radi dobijanja intermedijera 173 (250 mg, prinos 85,3%) kao sirovog proizvoda. [0544] A mixture of intermediate 172 (200 mg, ≈0.282 mmol) in TFA (5 ml) was stirred at 60 °C for 1 h. The mixture was evaporated under vacuum to give intermediate 173 (250 mg, 85.3% yield) as crude product.

Primer A51 Example A51

Priprema intermedijera 174 Preparation of intermediates 174

[0545] [0545]

[0546] 3-brom-7-jod-hinolin (5,99 g, 17,7 mmol) rastvoren je u dihlormetanu (60 ml), zatim je u porcijama dodat m-CPBA (4,57 g, 26,5 mmol). Smeša je mešana na sobnoj temperaturi tokom 4 dana. Smeša je deaktivirana zasićenim vodenim rastvorom Na2S2O3(40 ml) i zasićenim vodenim rastvorom NaHCO3(pH do 6-7), zatim ekstrahovana dihlormetanom (50 [0546] 3-Bromo-7-iodoquinoline (5.99 g, 17.7 mmol) was dissolved in dichloromethane (60 ml), then m-CPBA (4.57 g, 26.5 mmol) was added portionwise. The mixture was stirred at room temperature for 4 days. The mixture was deactivated with a saturated aqueous Na2S2O3 solution (40 ml) and a saturated aqueous NaHCO3 solution (pH up to 6-7), then extracted with dichloromethane (50

2 2

ml x 3). Organska faza je isprana pomoću H2O (50 ml), osušena anhidrovanim Na2SO4i uparena pod sniženim pritiskom. Ostatak je prečišćen na koloni silika gela (eluent: petrol etar/etil acetat = 10/1 do 1/1) radi dobijanja željenog proizvoda intermedijera 174 (1,9 g, prinos 14,1%) kao žute čvrste supstance. ml x 3). The organic phase was washed with H 2 O (50 ml), dried with anhydrous Na 2 SO 4 and evaporated under reduced pressure. The residue was purified on a silica gel column (eluent: petroleum ether/ethyl acetate = 10/1 to 1/1) to give the desired product intermediate 174 (1.9 g, yield 14.1%) as a yellow solid.

Priprema intermedijera 175 Preparation of intermediates 175

[0547] [0547]

[0548] U rastvor intermedijera 174 (2,9 g, 8,29 mmol) u hloroformu (60 ml) dodat je fosforil trihlorid (8,3 g, 54,1 mmol). Smeša je mešana na 80°C tokom 12 h. Smeša je uparena pod sniženim pritiskom radi dobijanja sirovog proizvoda. Sirovi proizvod je prečišćen hromatografijom na koloni (eluent: petrol etar/etil acetat = 10/1 do 1/1). Željene frakcije su sakupljene i koncentrovane radi dobijanja proizvoda intermedijera 175 (1,3 g, prinos 41,5%) kao bele čvrste supstance. [0548] To a solution of intermediate 174 (2.9 g, 8.29 mmol) in chloroform (60 ml) was added phosphoryl trichloride (8.3 g, 54.1 mmol). The mixture was stirred at 80°C for 12 h. The mixture was evaporated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (eluent: petroleum ether/ethyl acetate = 10/1 to 1/1). The desired fractions were collected and concentrated to give the product intermediate 175 (1.3 g, 41.5% yield) as a white solid.

Priprema intermedijera 176 Preparation of intermediates 176

[0549] [0549]

[0550] 4-metoksibenzilamin (1,34 g, 9,78 mmol) dodat je u smešu intermedijera 175 (0,8 g, ≈1,95 mmol) u etanolu (10 ml). Smeša je zagrevana u zaptivenoj epruveti na 100°C tokom 12 h. Smeša je uparena pod vakuumom radi dobijanja sirovog proizvoda. Proizvod je prečišćen hromatografijom na koloni (elucioni gradijent: etil acetat/petrol etar od 0/1 do 1/10). Željene [0550] 4-Methoxybenzylamine (1.34 g, 9.78 mmol) was added to a mixture of intermediate 175 (0.8 g, ≈1.95 mmol) in ethanol (10 mL). The mixture was heated in a sealed tube at 100°C for 12 h. The mixture was evaporated under vacuum to give the crude product. The product was purified by column chromatography (elution gradient: ethyl acetate/petroleum ether from 0/1 to 1/10). Desired

2 2

frakcije su sakupljene i koncentrovane radi dobijanja proizvoda intermedijera 176 (600 mg, prinos 51,6%) kao ulja. fractions were collected and concentrated to give the product intermediate 176 (600 mg, 51.6% yield) as an oil.

Priprema intermedijera 177 Preparation of intermediates 177

[0551] [0551]

[0552] Smeša intermedijera 38 (44 mg, 0,138 mmol) u 9-BBN (1,3 ml, 0,69 mmol, 0,5 M u THF-u) refluktovana je tokom 1 h u atmosferi N2. Smeša je ohlađena na sobnu temperaturu, zatim je dodat K3PO4(87 mg, 0,413 mmol) u H2O (1 ml), pa onda THF (5 ml), intermedijer 176 (122,727 mg, ≈0,206 mmol) i [1,1'-bis(difenilfosfino)ferocen]dihlorpaladijum(II) (4,48 mg, 0,007 mmol). Reakciona smeša je refluktovana tokom 3 sata. Smeša je koncentrovana. Ostatak je rastvoren u etil acetatu (40 ml), ispran vodom (6 ml), zasićenim vodenim rastvorom soli (6 ml). Organska faza je osušena iznad Na2SO4, filtrirana i koncentrovana radi dobijanja sirovog intermedijera 177 frakcije 1 (120 mg, prinos 71,5%). [0552] A mixture of intermediate 38 (44 mg, 0.138 mmol) in 9-BBN (1.3 mL, 0.69 mmol, 0.5 M in THF) was refluxed for 1 h under N 2 . The mixture was cooled to room temperature, then K3PO4 (87 mg, 0.413 mmol) in H2O (1 mL) was added, followed by THF (5 mL), intermediate 176 (122.727 mg, ≈0.206 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (4.48 mg, 0.007 mmol). The reaction mixture was refluxed for 3 hours. The mixture is concentrated. The residue was dissolved in ethyl acetate (40 ml), washed with water (6 ml), saturated aqueous salt solution (6 ml). The organic phase was dried over Na2SO4, filtered and concentrated to give crude intermediate 177 fraction 1 (120 mg, 71.5% yield).

[0553] Smeša intermedijera 38 (233,7 mg, 0,73 mmol) u 9-BBN (7,31 ml, 3,65 mmol, 0,5 M u THF-u) refluktovana je tokom 1 h u atmosferi N2. Smeša je ohlađena na sobnu temperaturu, zatim je dodat K3PO4(87 mg, 0,413 mmol) u H2O (1 ml), pa onda THF (5 ml), intermedijer 176 (478 mg, ≈0,80 mmol) i [1,1'-bis(difenilfosfino)ferocen]dihlorpaladijum(II) (23,8 mg, 0,037 mmol). Reakciona smeša je refluktovana tokom 3 sata. Smeša je koncentrovana. Ostatak je rastvoren u etil acetatu (40 ml), ispran vodom (6 ml), zasićenim vodenim rastvorom soli (6 ml). Organska faza je osušena iznad Na2SO4, filtrirana i koncentrovana do sirovog intermedijera 177 frakcija 2 (600 mg, prinos 63,1%). [0553] A mixture of intermediate 38 (233.7 mg, 0.73 mmol) in 9-BBN (7.31 ml, 3.65 mmol, 0.5 M in THF) was refluxed for 1 h under N 2 . The mixture was cooled to room temperature, then K3PO4 (87 mg, 0.413 mmol) in H2O (1 mL) was added, followed by THF (5 mL), intermediate 176 (478 mg, ≈0.80 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (23.8 mg, 0.037 mmol). The reaction mixture was refluxed for 3 hours. The mixture is concentrated. The residue was dissolved in ethyl acetate (40 ml), washed with water (6 ml), saturated aqueous salt solution (6 ml). The organic phase was dried over Na2SO4, filtered and concentrated to crude intermediate 177 fraction 2 (600 mg, 63.1% yield).

[0554] Dve frakcije su kombinovane i prečišćene hromatografijom na koloni (elucioni gradijent: etil acetat/petrol etar od 1/10 do 1/1). Željene frakcije su sakupljene i koncentrovane radi dobijanja intermedijera 177 (300 mg, prinos 61,0%) kao čvrste supstance. [0554] The two fractions were combined and purified by column chromatography (elution gradient: ethyl acetate/petroleum ether from 1/10 to 1/1). The desired fractions were collected and concentrated to give intermediate 177 (300 mg, 61.0% yield) as a solid.

2 2

Priprema intermedijera 178 Preparation of intermediates 178

[0555] [0555]

[0556] Smeša intermedijera 177 (300 mg, ≈0,446 mmol) i NH3.H2O (10 ml) u dioksanu (10 ml) mešana je u zaptivenoj epruveti na 120°C tokom 14 h. Ova reakcija je uparena pod vakuumom radi dobijanja intermedijera 178 (250 mg, prinos 87,1%) kao ulja. [0556] A mixture of intermediate 177 (300 mg, ≈0.446 mmol) and NH 3 .H 2 O (10 ml) in dioxane (10 ml) was stirred in a sealed tube at 120 °C for 14 h. This reaction was evaporated under vacuum to give intermediate 178 (250 mg, 87.1% yield) as an oil.

Priprema intermedijera 179 Preparation of intermediates 179

[0557] [0557]

[0558] Smeša intermedijera 178 (250 mg, ≈0,388 mmol) u TFA (5 ml) mešana je na 50°C tokom 1 h. Smeša je uparena pod vakuumom radi dobijanja intermedijera 179 (350 mg, prinos 63,4%) kao ulja. [0558] A mixture of intermediate 178 (250 mg, ≈0.388 mmol) in TFA (5 ml) was stirred at 50 °C for 1 h. The mixture was evaporated under vacuum to give intermediate 179 (350 mg, 63.4% yield) as an oil.

Primer A52 Example A52

Priprema intermedijera 180 Preparation of intermediates 180

[0559] [0559]

2 2

[0560] 3-hlor-7-brom-hinolin (10 g, 41,2 mmol) rastvoren je u dihlormetanu (150 ml). Zatim je u porcijama dodat m-CPBA (7,83 g, 45,3 mmol). Smeša je mešana na 35°C tokom 16 sati. Smeša je sipana u zasićeni vodeni rastvor Na2SO3. Smeša je ekstrahovana pomoću CH2Cl2. Smeša je zatim isprana zasićenim vodenim rastvorom Na2SO3(50 ml x 2) i zasićenim vodenim rastvorom NaHCO3(50 ml x 2). Organska supstanca je osušena iznad anhidrovanog Na2SO4i koncentrovana. Bela čvrsta supstanca je istaložena i filtrirana radi dobijanja intermedijera 180 (10 g, prinos 78,8%) kao žute čvrste supstance. [0560] 3-Chloro-7-bromo-quinoline (10 g, 41.2 mmol) was dissolved in dichloromethane (150 ml). m-CPBA (7.83 g, 45.3 mmol) was then added in portions. The mixture was stirred at 35°C for 16 hours. The mixture was poured into a saturated aqueous solution of Na2SO3. The mixture was extracted with CH2Cl2. The mixture was then washed with saturated aqueous Na 2 SO 3 (50 ml x 2) and saturated aqueous NaHCO 3 (50 ml x 2). The organic substance was dried over anhydrous Na2SO4 and concentrated. The white solid was precipitated and filtered to afford intermediate 180 (10 g, 78.8% yield) as a yellow solid.

Priprema intermedijera 181 Preparation of intermediates 181

[0561] [0561]

[0562] U rastvor intermedijera 180 (6 g, 23,2 mmol) u hloroformu (30 ml) dodat je fosforil trihlorid (18,8 g, 122,5 mmol). Smeša je mešana na 80°C tokom 1 h. Smeša je polako sipana u vodu. Zatim je u smešu dodat zasićeni vodeni rastvor NaHCO3kako bi se pH promenio na približno 7. [0562] To a solution of intermediate 180 (6 g, 23.2 mmol) in chloroform (30 ml) was added phosphoryl trichloride (18.8 g, 122.5 mmol). The mixture was stirred at 80°C for 1 h. The mixture was slowly poured into the water. Saturated aqueous NaHCO3 was then added to the mixture to adjust the pH to approximately 7.

[0563] Smeša je ekstrahovana pomoću CH2Cl2(50 ml x 2) i osušena iznad anhidrovanog Na2SO4. Organska faza je koncentrovana. Sirovi proizvod je prečišćen hromatografijom na koloni (eluent: petrol etar/etil acetat = 1/0 do 4/1). Željene frakcije su sakupljene i koncentrovane radi dobijanja intermedijera 181 (5 g, prinos 72,3%). [0563] The mixture was extracted with CH 2 Cl 2 (50 ml x 2) and dried over anhydrous Na 2 SO 4 . The organic phase is concentrated. The crude product was purified by column chromatography (eluent: petroleum ether/ethyl acetate = 1/0 to 4/1). The desired fractions were collected and concentrated to give intermediate 181 (5 g, yield 72.3%).

Priprema intermedijera 182 Preparation of intermediates 182

[0564] [0564]

2 1 2 1

[0565] U NH3u H2O (10 ml) i dioksanu (15 ml) dodat je intermedijer 181 (1 g, 3,6 mmol). Smeša je zagrevana u zaptivenoj epruveti na 120°C tokom 16 h. Smeša je ekstrahovana pomoću EtOAc. Organski sloj je osušen anhidrovanim Na2SO4i koncentrovan. Ostatak je prečišćen hromatografijom na koloni (elucioni gradijent: etil acetat/petrol etar od 0/1 do 1/3). Željene frakcije su sakupljene i koncentrovane radi dobijanja proizvoda intermedijera 182 (650 mg, prinos 69,2%) kao ružičaste čvrste supstance. [0565] To NH 3 and H 2 O (10 ml) and dioxane (15 ml) was added intermediate 181 (1 g, 3.6 mmol). The mixture was heated in a sealed tube at 120°C for 16 h. The mixture was extracted with EtOAc. The organic layer was dried with anhydrous Na2SO4 and concentrated. The residue was purified by column chromatography (elution gradient: ethyl acetate/petroleum ether from 0/1 to 1/3). The desired fractions were collected and concentrated to give the product intermediate 182 (650 mg, 69.2% yield) as a pink solid.

Priprema intermedijera 183 Preparation of intermediates 183

[0566] [0566]

[0567] Smeša intermedijera 38 (100 mg, 0,313 mmol) u 9-BBN (2,19 ml, 1,09 mmol, 0,5 M u THF-u) refluktovana je tokom 1,5 h u atmosferi N2. Smeša je ohlađena na sobnu temperaturu, zatim je dodat K3PO4(199 mg, 0,938 mmol) u H2O (2 ml), pa onda THF(8 ml), intermedijer 182 (88,6 mg, 0,344 mmol) i Pd-118 (26,48 mg, 0,407 mmol). Smeša je refluktovana tokom 3 sata. Smeša je koncentrovana. Ostatak je rastvoren u vodi, ekstrahovan etil acetatom (20 x 2 ml) i ispran zasićenim vodenim rastvorom soli (10 x 2 ml). Organska faza je osušena sa Na2SO4, filtrirana i koncentrovana. Ostatak je prečišćen hromatografijom na koloni (elucioni gradijent: etil acetat/petrol etar od 0/1 do 1/3). Željene frakcije su sakupljene i koncentrovane radi dobijanja intermedijera 183 (100 mg, prinos 55,4%). [0567] A mixture of intermediate 38 (100 mg, 0.313 mmol) in 9-BBN (2.19 ml, 1.09 mmol, 0.5 M in THF) was refluxed for 1.5 h under N 2 . The mixture was cooled to room temperature, then K 3 PO 4 (199 mg, 0.938 mmol) in H 2 O (2 mL) was added, followed by THF (8 mL), intermediate 182 (88.6 mg, 0.344 mmol) and Pd-118 (26.48 mg, 0.407 mmol). The mixture was refluxed for 3 hours. The mixture is concentrated. The residue was dissolved in water, extracted with ethyl acetate (20 x 2 ml) and washed with brine (10 x 2 ml). The organic phase was dried with Na2SO4, filtered and concentrated. The residue was purified by column chromatography (elution gradient: ethyl acetate/petroleum ether from 0/1 to 1/3). The desired fractions were collected and concentrated to give intermediate 183 (100 mg, 55.4% yield).

Priprema intermedijera 184 Preparation of intermediates 184

2 2 2 2

[0569] Smeša intermedijera 183 (800 mg, ≈1,605 mmol) i NH3.H2O (10 ml) u dioksanu (10 ml) zagrevana je u zaptivenoj epruveti na 120°C tokom 48 h. Smeša je ekstrahovana pomoću EtOAc (30 ml x 3). Organska faza je koncentrovana radi dobijanja intermedijera 184 (800 g, prinos 90%). [0569] A mixture of intermediate 183 (800 mg, ≈1.605 mmol) and NH 3 .H 2 O (10 ml) in dioxane (10 ml) was heated in a sealed tube at 120 °C for 48 h. The mixture was extracted with EtOAc (30 mL x 3). The organic phase was concentrated to give intermediate 184 (800 g, yield 90%).

[0570] Sledeći intermedijeri su pripremljeni reakcionim protokolom koji je analogan protokolu korišćenom za pripremu intermedijera 184 koristeći odgovarajuće polazne supstance (Tabela 31). [0570] The following intermediates were prepared by a reaction protocol analogous to the protocol used to prepare intermediate 184 using the appropriate starting substances (Table 31).

Tabela 31: Table 31:

2 2

24 24

2 2

2 2

2 2

2 2

Primer A57 Example A57

Priprema intermedijera 316 Preparation of intermediates 316

[0571] [0571]

2 2

[0572] Intermedijer 433 (10,8 g, 35,96 mmol) rastvoren je u 60 ml THF i dodat je 0,5 M 9-BBN u THF-u (226,5 ml, 113,2 mmol)), i reakciona smeša je mešana tokom 2 sata. Dodat je K3PO4(38,1 g, 179,78 mmol) u 65 ml vode, i reakciona smeša je žustro mešana tokom 30 min. Dodati su intermedijer 314 (10,46 g, 35, 96 mmol) i [1,1'-bis(difenilfosfino)ferocen]dihlorpaladijum(ii), i reakciona smeša je degasirana. Dobijena smeša je mešana tokom 2 sata na 60°C i ostavljena da se ohladi na sobnu temperaturu preko noći. EtOAc je dodat u reakcionu smešu, organski sloj je ispran vodom i zasićenim vodenim rastvorom soli, osušen iznad MgSO4 i koncentrovan pod sniženim pritiskom radi dobijanja sirovog proizvoda. Ostatak je prečišćen pomoću HPLC na normalnoj fazi (stacionarna faza: silika gel tipa: 60A 25_40 µm (Merck), mobilna faza: gradijent od 95% dihlormetana, 5% metanola do 90% dihlormetana, 10% metanola). Željene frakcije su sakupljene i uparene. Ostatak je ponovo prečišćen pomoću HPLC na normalnoj fazi (stacionarna faza: silika gel tipa 60A 25_40 um (Merck), mobilna faza: izokratski 95% etil acetat i 5% etanol, dajući intermedijer 316 [0572] Intermediate 433 (10.8 g, 35.96 mmol) was dissolved in 60 mL of THF and 0.5 M 9-BBN in THF (226.5 mL, 113.2 mmol)) was added, and the reaction mixture was stirred for 2 hours. K 3 PO 4 (38.1 g, 179.78 mmol) in 65 mL water was added, and the reaction mixture was vigorously stirred for 30 min. Intermediate 314 (10.46 g, 35.96 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(ii) were added, and the reaction mixture was degassed. The resulting mixture was stirred for 2 hours at 60°C and allowed to cool to room temperature overnight. EtOAc was added to the reaction mixture, the organic layer was washed with water and brine, dried over MgSO4 and concentrated under reduced pressure to give the crude product. The residue was purified by normal phase HPLC (stationary phase: silica gel type: 60A 25-40 µm (Merck), mobile phase: gradient from 95% dichloromethane, 5% methanol to 90% dichloromethane, 10% methanol). The desired fractions were pooled and matched. The residue was repurified by normal phase HPLC (stationary phase: silica gel type 60A 25_40 µm (Merck), mobile phase: isocratic 95% ethyl acetate and 5% ethanol, giving intermediate 316

(7,9 g, prinos 43%). (7.9 g, yield 43%).

Primer A 99 Example A 99

Priprema intermedijera 528 Preparation of intermediates 528

2 2

[0574] Intermedijer 175 (630 mg, 1,71 mmol) rastvoren je u dioksanu (10 ml). Dodat je NH3.H2O (10 ml). Reakciona smeša je mešana na 120°C tokom 24 sata u zaptivenoj epruveti. Reakciona smeša je ekstrahovana pomoću EtOAc (50 ml x 3). Organski slojevi su kombinovani, osušeni pomoću Na2SO4i rastvarač je uparen radi dobijanja intermedijera 528 (380 mg, prinos 62%) kao čvrste supstance. [0574] Intermediate 175 (630 mg, 1.71 mmol) was dissolved in dioxane (10 ml). NH3.H2O (10 mL) was added. The reaction mixture was stirred at 120°C for 24 hours in a sealed tube. The reaction mixture was extracted with EtOAc (50 mL x 3). The organic layers were combined, dried over Na 2 SO 4 and the solvent was evaporated to afford intermediate 528 (380 mg, 62% yield) as a solid.

Priprema intermedijera 529 Preparation of intermediates 529

[0575] [0575]

[0576] Smeša intermedijera 433 (22 g, 72,7 mmol) u 9-BBN/THF (0,5 M rastvor u THF-u, 585 ml, 292,3 mmol) mešana je na 50°C tokom 1 sata u atmosferi N2. Smeša je ohlađena na sobnu temperaturu, i dodati su K3PO4(77,6 g, 365,6 mmol) i H2O (80 ml). Smeša je mešana na sobnoj temperaturi tokom 0,5 sati, zatim su dodati THF (95 ml), intermedijer 528 (22,9 g, 65,8 mmol) i Pd(dppf)Cl2(4,77 g, 7,30 mmol) u atmosferi N2. Dobijena smeša je mešana na 50°C tokom 3 sata. Smeša je koncentrovana. Ostatak je rastvoren u etil acetatu (120 ml). Organski sloj je ispran vodom (10 ml) i zasićenim vodenim rastvorom soli (10 ml). Organska faza je osušena iznad Na2SO4, filtrirana i koncentrovana. Ostatak je prečišćen hromatografijom na koloni silika gela (odnos petrol etar/etil acetat 1/1 do odnosa petrol etar/etil acetat 0/1). Čiste [0576] A mixture of intermediate 433 (22 g, 72.7 mmol) in 9-BBN/THF (0.5 M solution in THF, 585 ml, 292.3 mmol) was stirred at 50°C for 1 hour under N 2 . The mixture was cooled to room temperature, and K 3 PO 4 (77.6 g, 365.6 mmol) and H 2 O (80 mL) were added. The mixture was stirred at room temperature for 0.5 h, then THF (95 mL), intermediate 528 (22.9 g, 65.8 mmol) and Pd(dppf)Cl 2 (4.77 g, 7.30 mmol) were added under N 2 . The resulting mixture was stirred at 50°C for 3 hours. The mixture is concentrated. The residue was dissolved in ethyl acetate (120 ml). The organic layer was washed with water (10 ml) and brine (10 ml). The organic phase was dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate ratio 1/1 to petroleum ether/ethyl acetate ratio 0/1). Clean

2 1 2 1

frakcije su sakupljene, i rastvarač je uparen pod vakuumom radi dobijanja 23,5 g intermedijera 529. fractions were collected, and the solvent was evaporated under vacuum to give 23.5 g of intermediate 529.

Primer A53 Example A53

Priprema intermedijera 193 Preparation of intermediates 193

[0577] [0577]

[0578] U rastvor intermedijera 105 (256 mg, 0, 5 mmol) i ciklopropil boronske kiseline (107,5 mg, 1,25 mmol) u dioksanu (3 ml) na r.t. dodat je Pd(dppf)Cl2.CH2Cl2(41 mg, 0,05 mmol). Azot je produvan kroz reakcionu smešu tokom jednog minuta, zatim su dodati K2CO3(174 mg, 1,25 mmol) i voda (0,2 ml), i azot je ponovo produvan kroz reakcionu smešu tokom jednog minuta. Reakciona smeša je zagrevana u zatvorenom sudu do 100°C tokom 16 h. Reakciona smeša je filtrirana preko dekalita i uparena do suva. Ostatak je prečišćen pomoću prep. HPLC (stacionarna faza: RP XBridge Prep C18 OBD-10 µm,50 x150 mm, mobilna faza: 0,25% NH4HCO3rastvor u vodi, CH3CN, dajući intermedijer 193 (110 mg, 46,5%) [0578] To a solution of intermediate 105 (256 mg, 0.5 mmol) and cyclopropyl boronic acid (107.5 mg, 1.25 mmol) in dioxane (3 ml) at r.t. Pd(dppf)Cl2.CH2Cl2 (41 mg, 0.05 mmol) was added. Nitrogen was flushed through the reaction mixture for one minute, then K 2 CO 3 (174 mg, 1.25 mmol) and water (0.2 mL) were added, and nitrogen was again flushed through the reaction mixture for one minute. The reaction mixture was heated in a closed vessel to 100°C for 16 h. The reaction mixture was filtered through decalite and evaporated to dryness. The residue was purified using prep. HPLC (stationary phase: RP XBridge Prep C18 OBD-10 µm, 50 x 150 mm, mobile phase: 0.25% NH4HCO3 aqueous solution, CH3CN, giving intermediate 193 (110 mg, 46.5%)

Primer A58 Example A58

Korak 1 Step 1

Priprema intermedijera 434 Preparation of intermediates 434

[0579] [0579]

2 2 2 2

[0580] 2-brom malonaldehid (2,1 g, 13,96 mmol) dodat je u porcijama u rastvor 4-hlor-3-metoksianilina (2,0 g, 12,69 mmol) u EtOH (100 ml) na 0°C u atmosferi N2. Nakon mešanja na sobnoj temperaturi tokom 2 h, smeša je koncentrovana radi dobijanja intermedijera 434 (4,0 g, prinos 69,5%) koji je korišćen u sledećem koraku bez daljeg prečišćavanja. [0580] 2-Bromomalonaldehyde (2.1 g, 13.96 mmol) was added portionwise to a solution of 4-chloro-3-methoxyaniline (2.0 g, 12.69 mmol) in EtOH (100 mL) at 0°C under N2 atmosphere. After stirring at room temperature for 2 h, the mixture was concentrated to give intermediate 434 (4.0 g, yield 69.5%) which was used in the next step without further purification.

[0581] Sledeći intermedijeri su pripremljeni reakcionim protokolom koji je analogan protokolu korišćenom za pripremu intermedijera 434 koristeći odgovarajuće polazne supstance (Tabela 32). [0581] The following intermediates were prepared by a reaction protocol analogous to the protocol used to prepare intermediate 434 using the appropriate starting substances (Table 32).

Tabela 32: Table 32:

Korak 2 Step 2

Priprema intermedijera 437 Preparation of intermediates 437

[0582] [0582]

2 2

[0583] Reakcija je dva puta izvršena. [0583] The reaction was carried out twice.

[0584] Smeša intermedijera 434 (1,0 g, 3,44 mmol) i PPA (1,0 g) u EtOH (20 ml) zagrevana je na 95°C u epruveti za mikrotalasnu pećnicu tokom 1 h. Dve reakcione smeše su kombinovane i koncentrovane. Ostatak je razblažen vodom i ekstrahovan pomoću CH2Cl2(50 ml x 5). Organska faza je isprana vod. NaHCO3, zasićenim vodenim rastvorom soli, osušena iznad Na2SO4, filtrirana i koncentrovana. Ostatak je prečišćen hromatografijom na koloni (eluent: petrol etar/EtOAc 85/15). Željene frakcije su sakupljene i koncentrovane radi dobijanja intermedijera 437 (0,77 g, prinos 41%) kao žute čvrste supstance. [0584] A mixture of intermediate 434 (1.0 g, 3.44 mmol) and PPA (1.0 g) in EtOH (20 mL) was heated at 95 °C in a microwave oven tube for 1 h. The two reaction mixtures were combined and concentrated. The residue was diluted with water and extracted with CH 2 Cl 2 (50 ml x 5). The organic phase was washed with water. NaHCO3, saturated aqueous salt solution, dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography (eluent: petroleum ether/EtOAc 85/15). The desired fractions were collected and concentrated to afford intermediate 437 (0.77 g, 41% yield) as a yellow solid.

[0585] Sledeći intermedijeri su pripremljeni reakcionim protokolom koji je analogan protokolu korišćenom za pripremu intermedijera 437 koristeći odgovarajuće polazne supstance (Tabela 33). [0585] The following intermediates were prepared by a reaction protocol analogous to the protocol used for the preparation of intermediate 437 using the appropriate starting substances (Table 33).

Tabela 33: Table 33:

Korak 3 Step 3

Priprema intermedijera 200 Preparation of intermediates 200

2 4 2 4

[0587] BBr3(1,6 ml, 16,60 mmol) dodat je u rastvor intermedijera 437 (1,28 g, 4,70 mmol) u CHCl3(25 ml) na 0°C. Reakciona smeša je refluktovana tokom 48 sati. Reakciona smeša je podešena na pH 7 pomoću zas. rastvora natrijum hidrogen karbonata. Smeša je koncentrovana sve dok CHCl3nije uklonjen. Dobijena smeša je filtrirana radi dobijanja intermedijera 200 (1,1 g, prinos 91%) kao čvrste supstance. [0587] BBr 3 (1.6 mL, 16.60 mmol) was added to a solution of intermediate 437 (1.28 g, 4.70 mmol) in CHCl 3 (25 mL) at 0 °C. The reaction mixture was refluxed for 48 hours. The reaction mixture was adjusted to pH 7 using sat. sodium hydrogen carbonate solution. The mixture was concentrated until the CHCl3 was removed. The resulting mixture was filtered to give intermediate 200 (1.1 g, 91% yield) as a solid.

[0588] Sledeći intermedijeri su pripremljeni reakcionim protokolom koji je analogan protokolu korišćenom za pripremu intermedijera 200 koristeći odgovarajuće polazne supstance (Tabela 34). [0588] The following intermediates were prepared by a reaction protocol analogous to the protocol used to prepare intermediate 200 using the appropriate starting substances (Table 34).

Tabela 34: Table 34:

Primer A59 Example A59

Korak 1 Step 1

2 2

Priprema intermedijera 440 Preparation of intermediate 440

[0589] [0589]

[0590] Smeša intermedijera 437 (720 mg, 2,64 mmol), tetrametil amonijum hlorida (2,90 g, 26,42 mmol), bakar(I) oksida (378,0 mg, 2,64 mmol) i L-prolina (608,3 mg, 5,28 mmol) u EtOH (15 ml) mešana je na 110°C u epruveti za mikrotalasnu pećnicu tokom 60 min. Smeša je filtrirana, i filtrat je koncentrovan. Ostatak je prečišćen hromatografijom (eluent: petrol etar/EtOAc 3/1). Željene frakcije su sakupljene i koncentrovane radi dobijanja intermedijera 440 (290 mg, prinos 48%) kao čvrste supstance. [0590] A mixture of intermediate 437 (720 mg, 2.64 mmol), tetramethyl ammonium chloride (2.90 g, 26.42 mmol), copper(I) oxide (378.0 mg, 2.64 mmol) and L-proline (608.3 mg, 5.28 mmol) in EtOH (15 mL) was stirred at 110°C in a microwave oven during 60 min. The mixture was filtered, and the filtrate was concentrated. The residue was purified by chromatography (eluent: petroleum ether/EtOAc 3/1). The desired fractions were collected and concentrated to give intermediate 440 (290 mg, 48% yield) as a solid.

Korak 2 Step 2

Priprema intermedijera 216 Preparation of intermediates 216

[0591] [0591]

[0592] BBr3(2,34 ml, 24,5 mmol) dodat je u rastvor intermedijera 440 (280 mg, 1,23 mmol) u ClCH2CH2Cl (15 ml) na 0°C. Reakciona smeša je refluktovana preko noći. Reakciona smeša je podešena na pH 7 pomoću zas. rastvora natrijum hidrogen karbonata. Smeša je koncentrovana sve dok ClCH2CH2Cl nije uklonjen. Dobijena čvrsta supstanca je filtrirana radi dobijanja intermedijera 216 (250 mg, prinos 87,5%). [0592] BBr 3 (2.34 mL, 24.5 mmol) was added to a solution of intermediate 440 (280 mg, 1.23 mmol) in ClCH 2 CH 2 Cl (15 mL) at 0 °C. The reaction mixture was refluxed overnight. The reaction mixture was adjusted to pH 7 using sat. sodium hydrogen carbonate solution. The mixture was concentrated until the ClCH2CH2Cl was removed. The resulting solid was filtered to give intermediate 216 (250 mg, 87.5% yield).

Primer A60 Example A60

2 2

Korak 1 Step 1

Priprema intermedijera 441 Preparation of intermediates 441

[0593] [0593]

[0594] Hinolin-2,7-diol (20 g, 124,1 mmol, 1,0 ekv.) prenet je u DMF (40 ml), na sobnoj temperaturi je dodat POCl3(107,7 g, 702,5 mmol, 5,7 ekv.). Reakciona smeša je mešana na 70°C tokom 1 h. Rastvarač je uklonjen pod sniženim pritiskom, ostatak je polako sipan u vodu (300 ml) na 0°C. U rastvor je dodat zasićeni vod. Na2CO3do pH = 8. Smeša je ekstrahovana etil acetatom, 1000 ml x 2. Organski sloj je ispran sa 1000 ml zasićenog vodenog rastvora soli i koncentrovan pod vakuumom radi dobijanja proizvoda intermedijera 441 (20 g, prinos 88%) kao čvrste supstance. [0594] Quinoline-2,7-diol (20 g, 124.1 mmol, 1.0 eq.) was taken up in DMF (40 mL), POCl 3 (107.7 g, 702.5 mmol, 5.7 eq.) was added at room temperature. The reaction mixture was stirred at 70°C for 1 h. The solvent was removed under reduced pressure, the residue was slowly poured into water (300 ml) at 0°C. Saturated water was added to the solution. Na2CO3 to pH = 8. The mixture was extracted with ethyl acetate, 1000 ml x 2. The organic layer was washed with 1000 ml of saturated aqueous salt solution and concentrated in vacuo to give the product intermediate 441 (20 g, 88% yield) as a solid.

Korak 2 Step 2

Priprema intermedijera 442 Preparation of intermediates 442

[0595] [0595]

[0596] Intermedijer 441 (2,5 g, 13,9 mmol, 1,0 ekv.) rastvoren je u DMF-u (25 ml), K2CO3(5,76 g, 41,76 mmol, 3 ekv.) i dodat je CH3I (5,2 g, 36,6 mmol, 2,63 ekv.). Reakciona smeša je mešana na 25°C tokom 12 h. Reakciona smeša je sipana u vodu (100 ml) i ekstrahovana pomoću EtOAc (150 ml). Organski sloj je ispran vodom (80 ml x 2), zasićenim vodenim rastvorom soli (800 ml) i osušen iznad anhidrovanog Na2SO4. Rastvarač je uklonjen pod [0596] Intermediate 441 (2.5 g, 13.9 mmol, 1.0 equiv) was dissolved in DMF (25 mL), K 2 CO 3 (5.76 g, 41.76 mmol, 3 equiv) and CH 3 I (5.2 g, 36.6 mmol, 2.63 equiv) was added. The reaction mixture was stirred at 25°C for 12 h. The reaction mixture was poured into water (100 mL) and extracted with EtOAc (150 mL). The organic layer was washed with water (80 ml x 2), brine (800 ml) and dried over anhydrous Na 2 SO 4 . The solvent was removed under

2 2

sniženim pritiskom radi dobijanja intermedijera 442 (2,6 g, prinos 96%) kao bele čvrste supstance. under reduced pressure to give intermediate 442 (2.6 g, 96% yield) as a white solid.

Korak 3 Step 3

Priprema intermedijera 443 Preparation of intermediates 443

[0597] [0597]

[0598] U rastvor intermedijera 442 (900 mg, 4,5 mmol, 1,0 ekv.), NH2Bn (0,578 g, 5,4 mmol, 1,2 ekv.) i Cs2CO3(2,93 g, 9 mmol, 2,0 ekv.) u DMF-u (5 ml) dodati su Pd2(dba)3(412 mg, 0,45 mmol, 0,1 ekv.) i BINAP (280 mg, 0,45 mmol, 0,1 ekv.). Dobijena smeša je mešana na 100°C u atmosferi N2tokom 12 h. Rastvarač je uklonjen pod sniženim pritiskom, ostatak je trituriran pomoću EtOAc (100 ml) i vode (100 ml). Vodeni sloj je ekstrahovan pomoću EtOAc (100 ml). Kombinovani organski slojevi su isprani zasićenim vodenim rastvorom soli (60 ml) i osušeni iznad anhidrovanog Na2SO4. Rastvarač je uklonjen pod sniženim pritiskom, ostatak je prečišćen hromatografijom na koloni (eluent: EtOAc/ petrol etar u odnosu 0/1 do 1/5) radi dobijanja intermedijera 443 (450 mg, prinos 37%) kao žute čvrste supstance. [0598] To a solution of intermediate 442 (900 mg, 4.5 mmol, 1.0 equiv.), NH2Bn (0.578 g, 5.4 mmol, 1.2 equiv.), and Cs2CO3 (2.93 g, 9 mmol, 2.0 equiv.) in DMF (5 mL) was added Pd2(dba)3 (412 mg, 0.45 mmol, 1.2 equiv.). 0.1 eq.) and BINAP (280 mg, 0.45 mmol, 0.1 eq.). The resulting mixture was stirred at 100°C in an N2 atmosphere for 12 h. The solvent was removed under reduced pressure, the residue was triturated with EtOAc (100 mL) and water (100 mL). The aqueous layer was extracted with EtOAc (100 mL). The combined organic layers were washed with brine (60 mL) and dried over anhydrous Na 2 SO 4 . The solvent was removed under reduced pressure, the residue was purified by column chromatography (eluent: EtOAc/petroleum ether 0/1 to 1/5) to give intermediate 443 (450 mg, 37% yield) as a yellow solid.

Korak 4 Step 4

Priprema intermedijera 231 Preparation of intermediates 231

[0599] [0599]

2 2

[0600] Intermedijer 443 (500 mg, 1,78 mmol, 1,0 ekv.) i piridin hidrohlorid (3,2 g, 28 mmol, 16 ekv.) stavljeni su u epruvetu. Reakciona smeša je mešana na 180°C tokom 2 h. Reakciona smeša je ohlađena na sobnu temperaturu. Reakciona smeša je rastvorena u 25 ml DCM i 25 ml H2O, i pH je podešen na oko 8-9 postepenim dodavanjem čvrstog K2CO3, i slojevi su razdvojeni. Vodeni sloj je ekstrahovan pomoću DCM (20 ml x 3). Kombinovani organski slojevi su osušeni (Na2SO4), filtrirani, i rastvarač je koncentrovan pod vakuumom radi dobijanja intermedijera 231 (440 mg, prinos 96%) kao ulja koje je korišćeno u sledećem koraku bez daljeg prečišćavanja. [0600] Intermediate 443 (500 mg, 1.78 mmol, 1.0 eq.) and pyridine hydrochloride (3.2 g, 28 mmol, 16 eq.) were placed in a test tube. The reaction mixture was stirred at 180°C for 2 h. The reaction mixture was cooled to room temperature. The reaction mixture was dissolved in 25 ml DCM and 25 ml H 2 O, and the pH was adjusted to about 8-9 by the gradual addition of solid K 2 CO 3 , and the layers were separated. The aqueous layer was extracted with DCM (20 ml x 3). The combined organic layers were dried (Na 2 SO 4 ), filtered, and the solvent was concentrated in vacuo to afford intermediate 231 (440 mg, 96% yield) as an oil which was used in the next step without further purification.

Primer A61 Example A61

Korak 1 Step 1

Priprema intermedijera 444 Preparation of intermediates 444

[0601] [0601]

[0602] Smeša CuI (6,80 g, 35,84 mmol), CsF (14,15 g, 93,18 mmol) 1-jod-2-metoksi-4-nitrobenzena (10 g, 35,84 mmol) i sulfolana (20 ml) žustro je mešana na 45°C. U ovu smešu je ukapavanjem dodat trimetil(trifluormetil)silan (13,25 g, 93,18 mmol) tokom 4 sata koristeći špric pumpu, i dobijena smeša je mešana na 45°C tokom 18 sati. Smeša je razblažena etil acetatom (500 ml) i mešana sa celitom tokom 5 min. Reakciona smeša je filtrirana kroz sloj celita, razblažena etil acetatom (500 ml). Organski sloj je ispran sa 10% NH4OH, 1,0 N HCl, zasićenim vodenim rastvorom soli, osušen iznad Na2SO4, filtriran i koncentrovan radi dobijanja sirovog proizvoda. Sirovi proizvod je prečišćen hromatografijom (etil acetat/petrol etar 0/1 do 1/4) radi dobijanja intermedijera 444 (8 g, prinos 91%) kao bele čvrste supstance. [0602] A mixture of CuI (6.80 g, 35.84 mmol), CsF (14.15 g, 93.18 mmol), 1-iodo-2-methoxy-4-nitrobenzene (10 g, 35.84 mmol) and sulfolane (20 mL) was stirred vigorously at 45°C. To this mixture was added dropwise trimethyl(trifluoromethyl)silane (13.25 g, 93.18 mmol) over 4 hours using a syringe pump, and the resulting mixture was stirred at 45°C for 18 hours. The mixture was diluted with ethyl acetate (500 ml) and stirred with celite for 5 min. The reaction mixture was filtered through a pad of celite, diluted with ethyl acetate (500 ml). The organic layer was washed with 10% NH 4 OH, 1.0 N HCl, brine, dried over Na 2 SO 4 , filtered and concentrated to give the crude product. The crude product was purified by chromatography (ethyl acetate/petroleum ether 0/1 to 1/4) to afford intermediate 444 (8 g, 91% yield) as a white solid.

Korak 2 Step 2

2 2

Priprema intermedijera 445 Preparation of intermediates 445

[0603] [0603]

[0604] Intermedijer 444 (7,1 g, 28,9 mmol) prenet je u metanol (100 ml i zatim je dodat 5% Pd/C (0,7 g). Smeša je hidrogenovana na sobnoj temperaturi tokom 48 sati u atmosferi H2(50 psi). Smeša je filtrirana i filtrat je uparen pod vakuumom radi dobijanja intermedijera 445 (7 g) kao bele čvrste supstance. [0604] Intermediate 444 (7.1 g, 28.9 mmol) was taken up in methanol (100 mL and then 5% Pd/C (0.7 g) was added. The mixture was hydrogenated at room temperature for 48 hours under H 2 (50 psi). The mixture was filtered and the filtrate was evaporated under vacuum to give intermediate 445 (7 g) as a white solid.

Korak 3 Step 3

Priprema intermedijera 446 Preparation of intermediates 446

[0605] [0605]

[0606] Smeša intermedijera 445 (6,2 g, 32,4 mmol), 2-brom malonaldehida (5,38 g, 35,7 mmol) i i-PrOH (120 ml) mešana je na sobnoj temperaturi tokom 5 min. Smeša je filtrirana, i filter pogača je isprana pomoću i-PrOH (10 ml). Filter pogača je osušena pod vakuumom radi dobijanja intermedijera 446 (6 g, prinos 51%) kao žute čvrste supstance. [0606] A mixture of intermediate 445 (6.2 g, 32.4 mmol), 2-bromomalonaldehyde (5.38 g, 35.7 mmol) and i-PrOH (120 mL) was stirred at room temperature for 5 min. The mixture was filtered, and the filter cake was washed with i-PrOH (10 mL). The filter cake was dried under vacuum to give intermediate 446 (6 g, 51% yield) as a yellow solid.

Korak 4 Step 4

Priprema intermedijera 447 Preparation of intermediates 447

[0608] Smeša intermedijera 446 (6 g, 18,5 mmol) i PPA (10 ml) u etanolu (150 ml) mešana je na 80°C preko noći. Smeša je uparena pod vakuumom. U smešu je dodata voda (100 ml) i voda je ekstrahovana etil acetatom (100 ml x 3). Organski slojevi su kombinovani i upareni pod vakuumom radi dobijanja sirovog proizvoda. Sirovi proizvod je prečišćen hromatografijom (etil acetat/petrol etar 0/1 do 1/10) radi dobijanja intermedijera 447 (3,3 g, prinos 54%) kao bele čvrste supstance. [0608] A mixture of intermediate 446 (6 g, 18.5 mmol) and PPA (10 ml) in ethanol (150 ml) was stirred at 80 °C overnight. The mixture was evaporated under vacuum. Water (100 ml) was added to the mixture and the water was extracted with ethyl acetate (100 ml x 3). The organic layers were combined and evaporated under vacuum to give the crude product. The crude product was purified by chromatography (ethyl acetate/petroleum ether 0/1 to 1/10) to afford intermediate 447 (3.3 g, 54% yield) as a white solid.

Korak 5 Step 5

Priprema intermedijera 210 Preparation of intermediates 210

[0609] [0609]

[0610] Smeša intermedijera 447 (1 g, 3,27 mmol) i piridin hidrohlorida (6 g, 51,9 mmol) mešana je na 210°C tokom 2 sata. Reakciona smeša je ohlađena na sobnu temperaturu. U smešu je dodata voda (20 ml). Smeša je ekstrahovana etil acetatom (20 ml x 3). Organski slojevi su kombinovani i upareni pod vakuumom radi dobijanja sirovog proizvoda. Sirovi proizvod je prečišćen hromatografijom (etil acetat/petrol etar 0/1 do 1/10) radi dobijanja intermedijera 210 (500 mg, prinos 49%) kao bele čvrste supstance. [0610] A mixture of intermediate 447 (1 g, 3.27 mmol) and pyridine hydrochloride (6 g, 51.9 mmol) was stirred at 210 °C for 2 h. The reaction mixture was cooled to room temperature. Water (20 ml) was added to the mixture. The mixture was extracted with ethyl acetate (20 ml x 3). The organic layers were combined and evaporated under vacuum to give the crude product. The crude product was purified by chromatography (ethyl acetate/petroleum ether 0/1 to 1/10) to give intermediate 210 (500 mg, 49% yield) as a white solid.

Primer A62 Example A62

Korak 1 Step 1

1 1

Priprema intermedijera 448 Preparation of intermediates 448

[0611] [0611]

[0612] 3-brom-7-hidroksihinolin (5 g, 22,3 mmol) rastvoren je u smeši DMF (50 ml) i CH3OH (50 ml). Dodati su [1,1'-bis(difenilfosfino)ferocen] dihlorpaladijum(ii) (0,816 g, 1,12 mmol) i N(C2H5)3(6,76 g, 66,9 mmol). Smeša je mešana na 140°C preko noći u atmosferi CO (3MPa). Smeša je uparena pod vakuumom. Ostatak je zatim prečišćen hromatografijom na koloni (eluent: petrol etar/etil acetat: odnos 10/1 do 0/1). Frakcije proizvoda su sakupljene i rastvarač je uparen radi dobijanja intermedijera 448 (2,5 g, prinos: 45,1%) kao žute čvrste supstance. [0612] 3-Bromo-7-hydroxyquinoline (5 g, 22.3 mmol) was dissolved in a mixture of DMF (50 mL) and CH 3 OH (50 mL). [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(ii) (0.816 g, 1.12 mmol) and N(C2H5)3 (6.76 g, 66.9 mmol) were added. The mixture was stirred at 140°C overnight under a CO atmosphere (3MPa). The mixture was evaporated under vacuum. The residue was then purified by column chromatography (eluent: petroleum ether/ethyl acetate: ratio 10/1 to 0/1). The product fractions were collected and the solvent was evaporated to give intermediate 448 (2.5 g, yield: 45.1%) as a yellow solid.

Korak 2 Step 2

Priprema intermedijera 449 Preparation of intermediates 449

[0613] [0613]

[0614] Cs2CO3(15,76 g, 48,37 mmol) dodat je u smešu intermedijera 448 (4 g, 16,1 mmol) i benzil bromida (2,76 g, 16,1 mmol) u DMF-u (50 ml) uz hlađenje ledom. Smeša je mešana na sobnoj temperaturi tokom 12 h. Reakciona smeša je filtrirana. Filtrat je koncentrovan pod vakuumom radi dobijanja sirovog proizvoda kao smeđe čvrste supstance. Sirovi proizvod je prečišćen hromatografijom na silika gelu (eluent: petrol etar/etil acetat: odnos 20/1 do 5/1) radi dobijanja intermedijera 449 (4,2 g, prinos: 82%) kao žute čvrste supstance. [0614] Cs 2 CO 3 (15.76 g, 48.37 mmol) was added to a mixture of intermediate 448 (4 g, 16.1 mmol) and benzyl bromide (2.76 g, 16.1 mmol) in DMF (50 mL) under ice-cooling. The mixture was stirred at room temperature for 12 h. The reaction mixture was filtered. The filtrate was concentrated under vacuum to give the crude product as a brown solid. The crude product was purified by silica gel chromatography (eluent: petroleum ether/ethyl acetate: ratio 20/1 to 5/1) to give intermediate 449 (4.2 g, yield: 82%) as a yellow solid.

2 2

Korak 3 Step 3

Priprema intermedijera 450 Preparation of intermediate 450

[0615] [0615]

[0616] LiAlH4(1,1 g, 28,3 mmol) dodat je u smešu intermedijera 449 (3 g, 9,45 mmol) u THF-u (60 ml) u atmosferi N2uz hlađenje ledom. Smeša je mešana na sobnoj temperaturi tokom 2 h. U smešu su dodati H2O (0,3 ml) i vod. NaOH (10%, 0,3 ml). Smeša je filtrirana. Filtrat je tretiran sa H2O (20 ml) i ekstrahovan sa EtOAc (40 ml x 2). Organski sloj je koncentrovan pod vakuumom radi dobijanja sirovog proizvoda kao čvrste supstance. Proizvod je prečišćen hromatografijom na koloni (eluent: petrol etar/EtOAc 1/2) radi dobijanja intermedijera 450 (822 mg, prinos: 32%) kao čvrste supstance. [0616] LiAlH 4 (1.1 g, 28.3 mmol) was added to a mixture of intermediate 449 (3 g, 9.45 mmol) in THF (60 mL) under N 2 under ice cooling. The mixture was stirred at room temperature for 2 h. To the mixture was added H 2 O (0.3 mL) and water. NaOH (10%, 0.3 ml). The mixture was filtered. The filtrate was treated with H 2 O (20 mL) and extracted with EtOAc (40 mL x 2). The organic layer was concentrated under vacuum to obtain the crude product as a solid. The product was purified by column chromatography (eluent: petroleum ether/EtOAc 1/2) to give intermediate 450 (822 mg, yield: 32%) as a solid.

Korak 4 Step 4

Priprema intermedijera 451 Preparation of intermediates 451

[0617] [0617]

[0618] 60% NaH (178 mg, 4,46 mmol,) dodat je u smešu intermedijera 450 (600 mg, 2,23 mmol) u THF-u (30 ml) u atmosferi N2uz hlađenje ledom. Dodat je CH3I (316 mg, 2,23 mmol) i reakcija je mešana na sobnoj temperaturi preko noći. U smešu su dodati EtOAc (40 ml) i voda (20 ml). Organska faza je razdvojena i osušena iznad Na2SO4, filtrirana i koncentrovana radi dobijanja sirovog proizvoda kao žutog ulja. Sirovi proizvod je prečišćen hromatografijom na koloni (eluent: petrol etar/EtOAc 1/2) radi dobijanja intermedijera 451 (620 mg, prinos: 98%) kao ulja. [0618] 60% NaH (178 mg, 4.46 mmol) was added to a mixture of intermediate 450 (600 mg, 2.23 mmol) in THF (30 mL) under N 2 under ice-cooling. CH 3 I (316 mg, 2.23 mmol) was added and the reaction was stirred at room temperature overnight. EtOAc (40 mL) and water (20 mL) were added to the mixture. The organic phase was separated and dried over Na 2 SO 4 , filtered and concentrated to give the crude product as a yellow oil. The crude product was purified by column chromatography (eluent: petroleum ether/EtOAc 1/2) to give intermediate 451 (620 mg, yield: 98%) as an oil.

Korak 5 Step 5

Priprema intermedijera 246 Preparation of intermediates 246

[0619] [0619]

[0620] BBr3(1 g, 4,29 mmol) dodat je u rastvor intermedijera 451 (600 mg, 2,15 mmol) u CH2Cl2(60 ml) na -70°C i reakcija je mešana tokom 30 min. U reakcionu smešu je dodat MeOH (40 ml) na -70°C. Reakciona smeša je mešana tokom 10 min. Smeša je koncentrovana pod vakuumom radi dobijanja intermedijera 246 (400 mg, prinos: 95%) kao žutog ulja. [0620] BBr 3 (1 g, 4.29 mmol) was added to a solution of intermediate 451 (600 mg, 2.15 mmol) in CH 2 Cl 2 (60 mL) at -70 °C and the reaction was stirred for 30 min. MeOH (40 mL) was added to the reaction mixture at -70°C. The reaction mixture was stirred for 10 min. The mixture was concentrated under vacuum to give intermediate 246 (400 mg, yield: 95%) as a yellow oil.

Primer A63 Example A63

Priprema intermedijera 263 Preparation of intermediates 263

[0621] [0621]

[0622] Intermedijer 441 (1,2 g, 6,68 mmol), 4-hlorbenzilamin (2,84 g, 20,0 mmol) i DIEA (1,73 g, 13,36 mmol) rastvoreni su u CH3CN (25 ml). Smeša je zagrevana na 120°C tokom 1,5 sati pomoću mikrotalasne pećnice. Smeša je koncentrovana pod sniženim pritiskom radi [0622] Intermediate 441 (1.2 g, 6.68 mmol), 4-chlorobenzylamine (2.84 g, 20.0 mmol) and DIEA (1.73 g, 13.36 mmol) were dissolved in CH 3 CN (25 mL). The mixture was heated at 120°C for 1.5 hours using a microwave oven. The mixture was concentrated under reduced pressure

4 4

dobijanja sirovog proizvoda kao smeđeg ulja. Sirovi proizvod je prečišćen hromatografijom na silika gelu (petrol etar/etil acetat: odnos od 20/1 do 3/1) radi dobijanja intermedijera 263 (1,2 g, prinos 35%) kao žute čvrste supstance. obtaining a crude product as a brown oil. The crude product was purified by silica gel chromatography (petroleum ether/ethyl acetate: 20/1 to 3/1 ratio) to afford intermediate 263 (1.2 g, 35% yield) as a yellow solid.

[0623] Sledeći intermedijeri su pripremljeni reakcionim protokolom koji je analogan protokolu korišćenom za pripremu intermedijera 263 koristeći odgovarajuće polazne supstance (Tabela 35). [0623] The following intermediates were prepared by a reaction protocol analogous to the protocol used for the preparation of intermediate 263 using the appropriate starting substances (Table 35).

Tabela 35: Table 35:

Primer A66 Example A66

Korak 1 Step 1

Priprema intermedijera 452 Preparation of intermediates 452

[0624] [0624]

[0625] U rastvor intermedijera 441 (5 g, 27,84 mmol) i imidazola (2,27 g, 33,5 mmol) u CH2Cl2(100 ml) dodat je TBDMSCl (5,04 g, 33,4 mmol) na 0°C. Reakcija je mešana na sobnoj temperaturi tokom 4 sata. Dodata je voda (100 ml) i smeša je ekstrahovana pomoću CH2Cl2(80 ml x 3). Organska faza je isprana zasićenim vodenim rastvorom soli (50 ml), osušena iznad anhidrovanog Na2SO4, filtrirana i koncentrovana radi dobijanja sirovog proizvoda. Sirovi proizvod je prečišćen hromatografijom na koloni silika gela (petrol etar/etil acetat: odnos 10/1). Željene frakcije su koncentrovane radi dobijanja intermedijera 452 (8,0 g, prinos 98%) kao ulja. [0625] To a solution of intermediate 441 (5 g, 27.84 mmol) and imidazole (2.27 g, 33.5 mmol) in CH 2 Cl 2 (100 ml) was added TBDMSCl (5.04 g, 33.4 mmol) at 0°C. The reaction was stirred at room temperature for 4 hours. Water (100 mL) was added and the mixture was extracted with CH 2 Cl 2 (80 mL x 3). The organic phase was washed with brine (50 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated to give the crude product. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate: ratio 10/1). The desired fractions were concentrated to give intermediate 452 (8.0 g, 98% yield) as an oil.

Korak 2 Step 2

Priprema intermedijera 453 Preparation of intermediates 453

[0626] [0626]

[0627] Rastvor intermedijera 452 (5 g, 17,0 mmol), Pd(PPh3)2Cl2(1,19 g, 1,70 mmol) i Et3N (3,44 g, 34,0 mmol) u DMF-u (10 ml) i MeOH (60 ml) mešan je u autoklavu na sobnoj temperaturi u atmosferi CO (50 psi). Rastvor je zagrevan na 80°C preko noći. Reakciona smeša je zatim filtrirana. Filtrat je koncentrovan radi dobijanja sirovog proizvoda. Sirovi proizvod je prečišćen hromatografijom na koloni silika gela (petrol etar/etil acetat, od 20/1 do 1/1) radi dobijanja intermedijera 453 (3,4 g, prinos 98%) kao svetložute čvrste supstance. [0627] A solution of intermediate 452 (5 g, 17.0 mmol), Pd(PPh 3 ) 2 Cl 2 (1.19 g, 1.70 mmol) and Et 3 N (3.44 g, 34.0 mmol) in DMF (10 ml) and MeOH (60 ml) was stirred in an autoclave at room temperature under an atmosphere of CO (50 psi). The solution was heated to 80°C overnight. The reaction mixture was then filtered. The filtrate was concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate, 20/1 to 1/1) to afford intermediate 453 (3.4 g, 98% yield) as a pale yellow solid.

Korak 3 Step 3

Priprema intermedijera 454 Preparation of intermediates 454

[0628] [0628]

[0629] U rastvor intermedijera 453 (1,5 g, 7,38 mmol) i imidazola (0,60 g, 8,86 mmol) u CH2Cl2(80 ml) dodat je TBDMSCl (1,34 g, 8,86 mmol) na 0°C. [0629] To a solution of intermediate 453 (1.5 g, 7.38 mmol) and imidazole (0.60 g, 8.86 mmol) in CH 2 Cl 2 (80 ml) was added TBDMSCl (1.34 g, 8.86 mmol) at 0°C.

[0630] Reakcija je mešana na sobnoj temperaturi tokom 2 sata. Reakcija je sipana u vodu i ekstrahovana etil acetatom (150 ml x 3) i organska faza je isprana zasićenim vodenim rastvorom soli (80 ml). Organska faza je osušena iznad anhidrovanog Na2SO4, filtrirana i koncentrovana radi dobijanja sirovog proizvoda. Sirovi proizvod je prečišćen hromatografijom na koloni silika gela (petrol etar/etil acetat: odnos 5:1). Željene frakcije su koncentrovane radi dobijanja intermedijera 454 (2,4 g, prinos 97,5%) kao belog ulja. [0630] The reaction was stirred at room temperature for 2 hours. The reaction was poured into water and extracted with ethyl acetate (150 ml x 3) and the organic phase was washed with brine (80 ml). The organic phase was dried over anhydrous Na 2 SO 4 , filtered and concentrated to give the crude product. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate: ratio 5:1). The desired fractions were concentrated to give intermediate 454 (2.4 g, 97.5% yield) as a white oil.

Korak 4 Step 4

Priprema intermedijera 455 Preparation of intermediate 455

[0631] [0631]

[0632] U rastvor NaBH4(2,264 g, 59,85 mmol) u EtOH (20 ml) ohlađen na 0°C ukapavanjem je dodat rastvor intermedijera 454 (1,9 g, 5,98 mmol) u THF-u (20 ml) tokom 5 min u atmosferi N2. Rastvor je ostavljen da se zagreje na sobnu temperaturu i mešan je tokom 2 sata. U reakciju su dodati zasićeni vodeni rastvor NaHCO3(20 ml) i voda (50 ml). Smeša je ekstrahovana pomoću EtOAc (80 ml x 3). Kombinovani organski slojevi su isprani zasićenim vodenim rastvorom soli (50 ml), osušeni iznad Na2SO4, filtrirani i koncentrovani radi dobijanja sirovog proizvoda intermedijer 455 (1,2 g, prinos 66,5%). [0632] To a solution of NaBH4 (2.264 g, 59.85 mmol) in EtOH (20 ml) cooled to 0°C was added dropwise a solution of intermediate 454 (1.9 g, 5.98 mmol) in THF (20 ml) over 5 min under N2 atmosphere. The solution was allowed to warm to room temperature and was stirred for 2 hours. A saturated aqueous solution of NaHCO3 (20 ml) and water (50 ml) were added to the reaction. The mixture was extracted with EtOAc (80 mL x 3). The combined organic layers were washed with brine (50 mL), dried over Na 2 SO 4 , filtered and concentrated to afford crude intermediate 455 (1.2 g, 66.5% yield).

Korak 5 Step 5

Priprema intermedijera 456 Preparation of intermediates 456

[0633] [0633]

[0634] U rastvor intermedijera 455 (1,2 g, 4,15 mmol) i Et3N (1,26 g, 12,44 mmol) ohlađen u THF-u (20 ml) ukapavanjem je dodat MsCl (569,9 mg, 4,98 mmol) u atmosferi N2. Reakciona smeša je mešana na 0°C u atmosferi N2tokom 30 minuta. Dodati su dimetilamin hidrohlorid (1,69 g, 20,73 mmol, 5 ekv.) i Et3N (4,195 g, 10 ekv.). Reakciona smeša je mešana na sobnoj temperaturi tokom 2 dana. Dodata je voda (40 ml) i smeša je ekstrahovana etil acetatom (50 ml x 3). Organski slojevi su kombinovani, osušeni iznad Na2SO4, filtrirani i koncentrovani radi dobijanja sirovog proizvoda kao ulja. Sirovi proizvod je prečišćen hromatografijom na koloni silika gela (petrol etar/etil acetat: odnos 1/1). Željene frakcije su koncentrovane radi dobijanja intermedijera 456 (550 mg) kao ulja. [0634] To a solution of intermediate 455 (1.2 g, 4.15 mmol) and Et3N (1.26 g, 12.44 mmol) cooled in THF (20 ml) was added dropwise MsCl (569.9 mg, 4.98 mmol) under N2 atmosphere. The reaction mixture was stirred at 0°C under N2 for 30 minutes. Dimethylamine hydrochloride (1.69 g, 20.73 mmol, 5 equiv) and Et3N (4.195 g, 10 equiv) were added. The reaction mixture was stirred at room temperature for 2 days. Water (40 mL) was added and the mixture was extracted with ethyl acetate (50 mL x 3). The organic layers were combined, dried over Na 2 SO 4 , filtered and concentrated to give the crude product as an oil. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate: ratio 1/1). The desired fractions were concentrated to give intermediate 456 (550 mg) as an oil.

Korak 6 Step 6

Priprema intermedijera 212 Preparation of intermediates 212

[0635] [0635]

[0636] U rastvor intermedijera 456 (500 mg, 1,58 mmol) u THF-u (20 ml) ukapavanjem je dodat TBAF (1 M rastvor u THF-u, 1,58 ml, 1,58 mmol) na sobnoj temperaturi u atmosferi N2. Reakciona smeša je mešana na sobnoj temperaturi tokom 30 minuta. Reakciona smeša je sipana u vodu (40 ml) i ekstrahovana pomoću EtOAc (50 ml x 3). Organski slojevi su kombinovani, osušeni iznad Na2SO4, filtrirani i upareni radi dobijanja sirovog proizvoda. Sirovi proizvod je prečišćen pomoću TLC (CH2Cl2/MeOH: odnos 5/1) radi dobijanja intermedijera 212 (80 mg, prinos 22,5%) kao svetložutog ulja. [0636] To a solution of intermediate 456 (500 mg, 1.58 mmol) in THF (20 ml) was added dropwise TBAF (1 M solution in THF, 1.58 ml, 1.58 mmol) at room temperature under N 2 . The reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was poured into water (40 mL) and extracted with EtOAc (50 mL x 3). The organic layers were combined, dried over Na 2 SO 4 , filtered and evaporated to give the crude product. The crude product was purified by TLC (CH 2 Cl 2 /MeOH: 5/1 ratio) to give intermediate 212 (80 mg, 22.5% yield) as a pale yellow oil.

Primer A67 Example A67

Korak 1 Step 1

Priprema intermedijera 457 i intermedijera 458 Preparation of intermediate 457 and intermediate 458

[0638] 3-hlor-5-bromanilin (1 g, 4,84 mmol) rastvoren je u 75% H2SO4(10 ml). Zatim su dodati glicerol (1,11 g, 12,1 mmol) i nitrobenzen (0,59 g, 4,84 mmol). Reakciona smeša je mešana na 150°C tokom 3 sata u atmosferi N2. Dodat je EtOAc (50 ml) i smeša je podešena na pH 6-7 pomoću 30% rastvora NaOH u vodi. Čvrsta supstanca je uklonjena filtracijom kroz celit, i organski sloj je razdvojen i uparen. Ostatak je prečišćen fleš hromatografijom na koloni silika gela (elucioni gradijent: petrol etar/EtOAc od 20/1 do 5/1). Željene frakcije su sakupljene i rastvarač je uparen radi dobijanja smeše intermedijera 457 i intermedijera 458 (750 mg) kao bele čvrste supstance. [0638] 3-Chloro-5-bromoaniline (1 g, 4.84 mmol) was dissolved in 75% H 2 SO 4 (10 ml). Glycerol (1.11 g, 12.1 mmol) and nitrobenzene (0.59 g, 4.84 mmol) were then added. The reaction mixture was stirred at 150°C for 3 hours under N2 atmosphere. EtOAc (50 mL) was added and the mixture was adjusted to pH 6-7 with 30% NaOH in water. The solid was removed by filtration through celite, and the organic layer was separated and evaporated. The residue was purified by flash chromatography on a silica gel column (elution gradient: petroleum ether/EtOAc from 20/1 to 5/1). The desired fractions were collected and the solvent was evaporated to give a mixture of intermediate 457 and intermediate 458 (750 mg) as a white solid.

Korak 2 Step 2

Priprema intermedijera 459 i intermedijera 460 Preparation of intermediate 459 and intermediate 460

[0639] [0639]

[0640] Smeša intermedijera 457 i intermedijera 458 (750 mg), bis(pinakolato)dibora (942,5 mg, 3,7 mmol), Pd(dppf)Cl2(113,1 mg, 0,155 mmol) i KOAc (910,6 mg, 9,28 mmol) u THF-u (20 ml) mešana je na 60°C tokom 2 sata u atmosferi N2. Dodata je voda (30 ml), i smeša je ekstrahovana pomoću EtOAc (30 ml x 3). Organski slojevi su kombinovani, osušeni iznad Na2SO4, filtrirani i koncentrovani radi dobijanja smeše intermedijera 459 i intermedijera 460 (1,0 g) kao žutog ulja. [0640] A mixture of intermediate 457 and intermediate 458 (750 mg), bis(pinacolato)diboron (942.5 mg, 3.7 mmol), Pd(dppf)Cl 2 (113.1 mg, 0.155 mmol) and KOAc (910.6 mg, 9.28 mmol) in THF (20 mL) was stirred at 60 °C for 2 h under atmosphere. N2. Water (30 mL) was added, and the mixture was extracted with EtOAc (30 mL x 3). The organic layers were combined, dried over Na 2 SO 4 , filtered and concentrated to give a mixture of intermediate 459 and intermediate 460 (1.0 g) as a yellow oil.

Korak 3 Step 3

Priprema intermedijera 220a i intermedijera 220b Preparation of intermediate 220a and intermediate 220b

[0641] [0641]

[0642] U smešu intermedijera 459 i intermedijera 460 (1 g) u acetonu (10 ml) dodat je rastvor oksona (1,25 g 2,03 mmol) u H2O (10 ml) ukapavanjem u atmosferi N2na 0°C. Reakciona smeša je mešana na 0°C tokom 1 sata. Dodata je voda (20 ml) i smeša je ekstrahovana pomoću EtOAc (3 x 30 ml). Organski sloj je kombinovan, osušen iznad Na2SO4, filtriran i koncentrovan. Ostatak je trituriran uz EtOAc/petrol etar (1/10). Talog je uklonjen filtracijom i osušen radi dobijanja smeše intermedijera 220a i intermedijera 220b (150 mg) kao žute čvrste supstance. [0642] To a mixture of intermediate 459 and intermediate 460 (1 g) in acetone (10 ml) was added a solution of oxone (1.25 g 2.03 mmol) in H2O (10 ml) dropwise under an atmosphere of N2 at 0°C. The reaction mixture was stirred at 0°C for 1 hour. Water (20 mL) was added and the mixture was extracted with EtOAc (3 x 30 mL). The organic layers were combined, dried over Na 2 SO 4 , filtered and concentrated. The residue was triturated with EtOAc/petroleum ether (1/10). The precipitate was removed by filtration and dried to give a mixture of intermediate 220a and intermediate 220b (150 mg) as a yellow solid.

Primer A68 Example A68

Priprema intermedijera 218 Preparation of intermediates 218

[0643] [0643]

[0644] Smeša intermedijera 205 (400 mg, 1,55 mmol), Me4NCl (1,36 g, 12,4 mmol), Cu2O (88,5 mg, 0,62 mmol) i L-prolina (142,5 mg, 1,24 mmol) u EtOH (10 ml) mešana je na 110°C [0644] A mixture of intermediate 205 (400 mg, 1.55 mmol), Me 4 NCl (1.36 g, 12.4 mmol), Cu 2 O (88.5 mg, 0.62 mmol) and L-proline (142.5 mg, 1.24 mmol) in EtOH (10 mL) was stirred at 110°C.

1 1

tokom 120 min koristeći mikrotalasnu pećnicu sa jednim režimom. Reakciona smeša je koncentrovana i prečišćena hromatografijom na koloni (eluent: petrol etar/etil acetat: odnos 1/0 do 1/1). Frakcije proizvoda su sakupljene, i rastvarač je uparen radi dobijanja intermedijera 218 (350 mg, 97%) kao žute čvrste supstance. for 120 min using a single mode microwave oven. The reaction mixture was concentrated and purified by column chromatography (eluent: petroleum ether/ethyl acetate: ratio 1/0 to 1/1). The product fractions were collected, and the solvent was evaporated to give intermediate 218 (350 mg, 97%) as a yellow solid.

Primer A69 Example A69

Priprema intermedijera 235 Preparation of intermediates 235

[0645] [0645]

[0646] Reakcija je obavljena dva puta. [0646] The reaction was performed twice.

[0647] U rastvor 3 brom-7-hidroksihinolina (500 mg, 2,23 mmol) u THF-u (10 ml) dodat je ciklopentilcink(II) bromid (0,5 M rastvor, 7,14 ml, 3,57 mmol), bis(tri-tercbutilfosfin)paladijum(O) (114,0 mg, 0,223 mmol) i t-BuOK (250,4 mg, 2,23 mmol) u atmosferi N2. Reakciona smeša je zagrevana na 100°C tokom 45 min u mikrotalasnoj pećnici. Reakciona smeša je ohlađena na sobnu temperaturu, filtrirana i koncentrovana pod sniženim pritiskom radi dobijanja sirovog proizvoda kao žutog ulja. Dva sirova proizvoda su kombinovana i prečišćena na koloni silika gela (petrol etar/etil acetat odnos: 5/1 do 1/1) radi dobijanja intermedijera 235 (300 mg) kao žute čvrste supstance. [0647] To a solution of 3 bromo-7-hydroxyquinoline (500 mg, 2.23 mmol) in THF (10 ml) was added cyclopentylzinc(II) bromide (0.5 M solution, 7.14 ml, 3.57 mmol), bis(tri-tertbutylphosphine)palladium(O) (114.0 mg, 0.223 mmol) and t-BuOK (250.4 mg, 0.223 mmol). 2.23 mmol) in an N2 atmosphere. The reaction mixture was heated at 100°C for 45 min in a microwave oven. The reaction mixture was cooled to room temperature, filtered and concentrated under reduced pressure to give the crude product as a yellow oil. The two crude products were combined and purified on a silica gel column (petroleum ether/ethyl acetate ratio: 5/1 to 1/1) to afford intermediate 235 (300 mg) as a yellow solid.

Priprema intermedijera 240 Preparation of intermediates 240

[0648] [0648]

11 11

[0649] Reakcija je obavljena dva puta. [0649] The reaction was performed twice.

[0650] U rastvor 3 brom-7-hidroksihinolina (700 mg 3,12 mmol) u THF-u (10 ml) dodat je izobutilcink(II) bromid (0,5 M rastvor, 9,37 ml, 4,69 mmol), bis(tri-tercbutilfosfin)paladijum(0) (319,3 mg 0,625 mmol) i t-BuOK (350,58 mg 3,12 mmol) u atmosferi N2. Reakciona smeša je zagrevana na 100°C tokom 45 min u mikrotalasnoj pećnici. Reakciona smeša je ohlađena na sobnu temperaturu, filtrirana i koncentrovana pod sniženim pritiskom radi dobijanja sirovog proizvoda. Dva sirova proizvoda su kombinovana i prečišćena na koloni silika gela (petrol etar/etil acetat odnos: 3/1 do 1/1) radi dobijanja intermedijera 240 (410 mg) kao žute čvrste supstance. [0650] To a solution of 3 bromo-7-hydroxyquinoline (700 mg 3.12 mmol) in THF (10 ml) was added isobutylzinc(II) bromide (0.5 M solution, 9.37 ml, 4.69 mmol), bis(tri-tertbutylphosphine)palladium(0) (319.3 mg 0.625 mmol) and t-BuOK (350.58 mg). 3.12 mmol) in an N2 atmosphere. The reaction mixture was heated at 100°C for 45 min in a microwave oven. The reaction mixture was cooled to room temperature, filtered and concentrated under reduced pressure to obtain the crude product. The two crude products were combined and purified on a silica gel column (petroleum ether/ethyl acetate ratio: 3/1 to 1/1) to afford intermediate 240 (410 mg) as a yellow solid.

Primer A98 Example A98

Korak 1: Step 1:

Priprema intermedijera 505 Preparation of intermediate 505

[0651] [0651]

[0652] 3-brom 7-metoksihinolin (5 g, 21 mmol) rastvoren je u dihlormetanu (50 ml). Zatim je 3-hlorperoksibenzojeva kiselina (5,116 g, 25,2 mmol) u frakcijama dodata u smešu na 0°C. Dobijena smeša je mešana na sobnoj temperaturi preko noći. Smeša je sipana u zas. vodeni rastvor Na2SO3(30 ml). Smeša je ekstrahovana dihlormetanom (50 ml x 2). Organska faza je zatim isprana zas. vodenim rastvorom NaHCO3(50 ml) i zasićenim vodenim rastvorom soli (50 ml). Organski sloj je osušen iznad anhidrovanog Na2SO4. Istaložila se bela čvrsta supstanca koja je filtrirana radi dobijanja intermedijera 505 (6,4 g, prinos 87%). [0652] 3-Bromo 7-methoxyquinoline (5 g, 21 mmol) was dissolved in dichloromethane (50 ml). Then 3-chloroperoxybenzoic acid (5.116 g, 25.2 mmol) was added in portions to the mixture at 0°C. The resulting mixture was stirred at room temperature overnight. The mixture was poured into the aqueous solution of Na2SO3 (30 ml). The mixture was extracted with dichloromethane (50 ml x 2). The organic phase was then washed sat. aqueous NaHCO3 solution (50 ml) and saturated aqueous salt solution (50 ml). The organic layer was dried over anhydrous Na2SO4. A white solid precipitated and was filtered to give intermediate 505 (6.4 g, 87% yield).

Korak 2: Step 2:

12 12

Priprema intermedijera 506 Preparation of intermediate 506

[0653] [0653]

[0654] Intermedijer 505 (6,4 g, 18,25 mmol) rastvoren je u hloroformu (100 ml). Zatim je dodat fosfor oksihlorid (20 ml) i reakciona smeša je refluktovana na 80°C tokom 3 sata. Rastvarač je uklonjen pod sniženim pritiskom radi dobijanja intermedijera 506 (5,8 g, prinos 97%) kao bele čvrste supstance koja je korišćena u sledećem koraku bez daljeg prečišćavanja. [0654] Intermediate 505 (6.4 g, 18.25 mmol) was dissolved in chloroform (100 mL). Phosphorus oxychloride (20 ml) was then added and the reaction mixture was refluxed at 80°C for 3 hours. The solvent was removed under reduced pressure to give intermediate 506 (5.8 g, 97% yield) as a white solid which was used in the next step without further purification.

Korak 3: Step 3:

Priprema intermedijera 507 Preparation of intermediate 507

[0655] [0655]

[0656] Smeša intermedijera 506 (3 g, 11 mmol) i NH3.H2O (20 ml) u dioksanu (20 ml) zagrevana je u zaptivenoj epruveti na 120°C tokom 72 h. Smeša je ekstrahovana pomoću CH2Cl2(50 ml x 3). Organska faza je koncentrovana pod vakuumom radi dobijanja sirovog proizvoda. Sirovi proizvod je prečišćen hromatografijom (etil acetat/petrol etar 0/20 do 1/20) radi dobijanja intermedijera 507 (0,9 g, prinos 32%) kao bele čvrste supstance. [0656] A mixture of intermediate 506 (3 g, 11 mmol) and NH 3 .H 2 O (20 ml) in dioxane (20 ml) was heated in a sealed tube at 120 °C for 72 h. The mixture was extracted with CH 2 Cl 2 (50 mL x 3). The organic phase was concentrated under vacuum to obtain the crude product. The crude product was purified by chromatography (ethyl acetate/petroleum ether 0/20 to 1/20) to afford intermediate 507 (0.9 g, 32% yield) as a white solid.

Korak 4: Step 4:

1 1

Priprema intermedijera 477 Preparation of intermediates 477

[0657] [0657]

[0658] Intermedijer 507 (1,2 g, 4,74 mmol) rastvoren je u CH2Cl2(12 ml). Zatim je žuta bistra reakcija ohlađena na 0°C i dodat je BBr3(23,75 g, 94,82 mmol). Reakciona smeša je mešana na sobnoj temperaturi tokom 16 sata. Reakcija je polako deaktivirana sa MeOH na 0°C i mešana na 15°C tokom 15 min. Crvena suspenzija je koncentrovana. Ostatak je podešen na pH 8 pomoću vodenog NaHCO3. Talog je filtriran i ispran pomoću H2O (10 ml). Filter pogača je osušena pod vakuumom radi dobijanja intermedijera 477 (1,1 g, prinos 97%) kao beličaste čvrste supstance. [0658] Intermediate 507 (1.2 g, 4.74 mmol) was dissolved in CH 2 Cl 2 (12 mL). The yellow clear reaction was then cooled to 0°C and BBr3 (23.75 g, 94.82 mmol) was added. The reaction mixture was stirred at room temperature for 16 hours. The reaction was slowly quenched with MeOH at 0°C and stirred at 15°C for 15 min. The red suspension is concentrated. The residue was adjusted to pH 8 with aqueous NaHCO3. The precipitate was filtered and washed with H 2 O (10 ml). The filter cake was dried under vacuum to give intermediate 477 (1.1 g, 97% yield) as an off-white solid.

Primer A99 Example A99

Korak 1: Step 1:

Priprema intermedijera 508 Preparation of intermediate 508

[0659] [0659]

[0660] Smeša 3-brom 7-metoksihinolina (10 g, 42 mmol), CuCl (20 g, 204 mmol), NaCl (20 g, 345 mmol) i N-metilpirolidin-2-ona (200 ml) zagrevana je na 120°C tokom 2 sata. Reakciona smeša je zatim mešana na 170°C tokom 2 sata. Reakcija je razblažena zasićenim vodenim rastvorom amonijum hlorida, dodat je etil acetat, i smeša je mešana da bi se proizvod rastvorio. [0660] A mixture of 3-bromo 7-methoxyquinoline (10 g, 42 mmol), CuCl (20 g, 204 mmol), NaCl (20 g, 345 mmol) and N-methylpyrrolidin-2-one (200 ml) was heated at 120°C for 2 hours. The reaction mixture was then stirred at 170°C for 2 hours. The reaction was diluted with saturated aqueous ammonium chloride, ethyl acetate was added, and the mixture was stirred to dissolve the product.

14 14

Smeša je filtrirana radi uklanjanja nerastvorljive supstance, i organska faza je razdvojena. Vodena faza je ekstrahovana etil acetatom (200 ml x 3), i nerastvorljiva supstanca je isprana toplim etil acetatom (200 ml x 3). Frakcije etil acetata su kombinovane, isprane vodom, osušene iznad Na2SO4i uparene pod sniženim pritiskom. Ostatak je prečišćen fleš hromatografijom (elucioni gradijent: EtOAc/petrol etar od 1/20 do 1/5) radi dobijanja intermedijera 508 (2 g, prinos 22%) kao bele čvrste supstance. The mixture was filtered to remove insoluble matter, and the organic phase was separated. The aqueous phase was extracted with ethyl acetate (200 ml x 3), and the insoluble material was washed with warm ethyl acetate (200 ml x 3). The ethyl acetate fractions were combined, washed with water, dried over Na 2 SO 4 and evaporated under reduced pressure. The residue was purified by flash chromatography (elution gradient: EtOAc/petroleum ether from 1/20 to 1/5) to give intermediate 508 (2 g, 22% yield) as a white solid.

Korak 2: Step 2:

Priprema intermedijera 509 Preparation of intermediate 509

[0661] [0661]

[0662] Intermedijer 508 (2 g, 10,3 mmol) rastvoren je u dihlormetanu (40 ml). Zatim je 3-hlorperoksibenzojeva kiselina (3,565 g, 20,65 mmol) u frakcijama dodata u smešu na 0°C. Dobijena smeša je mešana na sobnoj temperaturi preko noći. Smeša je sipana u zas. vodeni rastvor Na2SO3(30 ml). Smeša je ekstrahovana dihlormetanom (50 ml x 2). Organska faza je zatim isprana zas. vodenim rastvorom NaHCO3(50 ml) i zasićenim vodenim rastvorom soli (50 ml). Organski sloj je osušen iznad anhidrovanog Na2SO4. Bela čvrsta supstanca je istaložena i filtrirana radi dobijanja intermedijera 509 (2 g, prinos 83%). [0662] Intermediate 508 (2 g, 10.3 mmol) was dissolved in dichloromethane (40 mL). Then 3-chloroperoxybenzoic acid (3.565 g, 20.65 mmol) was added in fractions to the mixture at 0°C. The resulting mixture was stirred at room temperature overnight. The mixture was poured into the aqueous solution of Na2SO3 (30 ml). The mixture was extracted with dichloromethane (50 ml x 2). The organic phase was then washed sat. aqueous NaHCO3 solution (50 ml) and saturated aqueous salt solution (50 ml). The organic layer was dried over anhydrous Na2SO4. The white solid was precipitated and filtered to give intermediate 509 (2 g, 83% yield).

Korak 3: Step 3:

[0663] [0663]

1 1

[0664] Intermedijer 509 (2,4 g, 18,25 mmol) rastvoren je u hloroformu (50 ml). Zatim je dodat fosfor oksihlorid (10,5 g, 68,69 mmol), i reakciona smeša je refluktovana na 80°C tokom 2 sata. Reakciona smeša je polako sipana u vodu. Zatim je zas. vodeni rastvor NaHCO3dodat u smešu kako bi se pH promenio na ∼7. Reakciona smeša je ekstrahovana dihlormetanom (200 ml x 2) i organski sloj je osušen anhidrovanim Na2SO4. Organska faza je koncentrovana radi dobijanja intermedijera 510 (2,5 g, prinos 93%) kao bele čvrste supstance. [0664] Intermediate 509 (2.4 g, 18.25 mmol) was dissolved in chloroform (50 mL). Phosphorus oxychloride (10.5 g, 68.69 mmol) was then added, and the reaction mixture was refluxed at 80°C for 2 hours. The reaction mixture was slowly poured into water. Then sat. aqueous NaHCO3 solution added to the mixture to change the pH to ∼7. The reaction mixture was extracted with dichloromethane (200 mL x 2) and the organic layer was dried over anhydrous Na 2 SO 4 . The organic phase was concentrated to give intermediate 510 (2.5 g, 93% yield) as a white solid.

Korak 4: Step 4:

Priprema intermedijera 511 Preparation of intermediates 511

[0665] [0665]

[0666] Smeša intermedijera 510 (2,2 g, 9,64 mmol), benzofenon imina (1,78 g, 9,83 mmol), Pd(OAc)2(0,21 g, 0,96 mmol), BINAP (0,6 g, 0,96 mmol) Cs2CO3(6,28 g, 19,29 mmol) i toluena (50 ml) zagrevana je na 110°C tokom 48 sati u atmosferi N2. Katalizator je filtriran i rastvarač je uparen. Ostatak je prečišćen fleš hromatografijom na koloni silika gela (elucioni gradijent: EtOAc/petrol etar od 1/15 do 1/1). Frakcije proizvoda su sakupljene i rastvarač je uparen radi dobijanja intermedijera 511 (2 g, prinos 54%) kao ulja. [0666] A mixture of intermediate 510 (2.2 g, 9.64 mmol), benzophenone imine (1.78 g, 9.83 mmol), Pd(OAc) 2 (0.21 g, 0.96 mmol), BINAP (0.6 g, 0.96 mmol), Cs 2 CO 3 (6.28 g, 19.29 mmol) and toluene (50 mL) was heated at 110°C for 48 hours in an N2 atmosphere. The catalyst was filtered and the solvent was evaporated. The residue was purified by flash chromatography on a silica gel column (elution gradient: EtOAc/petroleum ether from 1/15 to 1/1). The product fractions were collected and the solvent was evaporated to give intermediate 511 (2 g, 54% yield) as an oil.

[0667] Korak 5: [0667] Step 5:

Priprema intermedijera 468 Preparation of intermediates 468

[0668] [0668]

1 1

[0669] Intermedijer 511 (2 g, 5,2 mmol) rastvoren je u CH2Cl2(100 ml). Zatim je žuta bistra reakcija ohlađena na 0°C i dodat je BBr3(20 g, 79,84 mmol). Reakciona smeša je mešana na sobnoj temperaturi tokom 14 sata. Reakciona smeša je podešena na pH 7 zas. rastvorom natrijum hidrogen karbonata i ekstrahovana pomoću EtOAc (3×300 ml). Kombinovani organski slojevi su razdvojeni, osušeni iznad Na2SO4, i rastvarač je uparen radi dobijanja intermedijera 468 (2 g, prinos 69,5%) kao bele čvrste supstance. [0669] Intermediate 511 (2 g, 5.2 mmol) was dissolved in CH 2 Cl 2 (100 mL). The yellow clear reaction was then cooled to 0°C and BBr3 (20 g, 79.84 mmol) was added. The reaction mixture was stirred at room temperature for 14 hours. The reaction mixture was adjusted to pH 7 sat. sodium hydrogen carbonate solution and extracted with EtOAc (3×300 ml). The combined organic layers were separated, dried over Na 2 SO 4 , and the solvent was evaporated to afford intermediate 468 (2 g, 69.5% yield) as a white solid.

Primer A70 Example A70

Priprema intermedijera 305 Preparation of intermediates 305

[0670] [0670]

[0671] Smeša 7-brom-2-hlorhinolina (2,45 g, 10,1 mmol) i 2,2,2-trifluoretilamina (5,0 g, 50,5 mol) u EtOH (60 ml) mešana je u zaptivenoj epruveti na 120°C preko noći. Reakciona smeša je tretirana vodenim rastvorom NaCl (80 ml) i ekstrahovana pomoću EtOAc (80 ml x 2). Organski slojevi su kombinovani i koncentrovani pod vakuumom radi dobijanja sirovog proizvoda. Sirovi proizvod je prečišćen hromatografijom na silika gelu (etil acetat/petrol etar 0/1 do 3/7) radi dobijanja intermedijera 305 (2,5 g, prinos 62,5%) kao bele čvrste supstance. [0671] A mixture of 7-bromo-2-chloroquinoline (2.45 g, 10.1 mmol) and 2,2,2-trifluoroethylamine (5.0 g, 50.5 mol) in EtOH (60 mL) was stirred in a sealed tube at 120°C overnight. The reaction mixture was treated with aqueous NaCl (80 mL) and extracted with EtOAc (80 mL x 2). The organic layers were combined and concentrated under vacuum to give the crude product. The crude product was purified by chromatography on silica gel (ethyl acetate/petroleum ether 0/1 to 3/7) to give intermediate 305 (2.5 g, yield 62.5%) as a white solid.

[0672] Sledeći intermedijeri su pripremljeni reakcionim protokolom koji je analogan protokolu korišćenom za pripremu intermedijera 305 koristeći odgovarajuće polazne supstance (Tabela 36). [0672] The following intermediates were prepared by a reaction protocol analogous to the protocol used to prepare intermediate 305 using the appropriate starting substances (Table 36).

1 1

Tabela 36: Table 36:

1 1

Primer A71 Example A71

Priprema intermedijera 338 Preparation of intermediates 338

[0673] [0673]

1 1

[0674] Smeša intermedijera 306 (520 mg, 0,95 mmol) i CH3NH2/EtOH (15 ml) u EtOH (15 ml) mešana je na 120°C preko noći u zaptivenoj epruveti. Reakcija je koncentrovana radi dobijanja intermedijera 338 (590 mg) koji je korišćen u sledećem koraku bez daljeg prečišćavanja. [0674] A mixture of intermediate 306 (520 mg, 0.95 mmol) and CH 3 NH 2 /EtOH (15 mL) in EtOH (15 mL) was stirred at 120 °C overnight in a sealed tube. The reaction was concentrated to give intermediate 338 (590 mg) which was used in the next step without further purification.

[0675] Sledeći intermedijeri su pripremljeni reakcionim protokolom koji je analogan protokolu korišćenom za pripremu intermedijera 338 koristeći odgovarajuće polazne supstance (Tabela 37). [0675] The following intermediates were prepared by a reaction protocol analogous to the protocol used to prepare intermediate 338 using the appropriate starting substances (Table 37).

Tabela 37: Table 37:

2 2

21 21

22 22

2 2

24 24

Primer A72 Example A72

Priprema intermedijera 353 Preparation of intermediates 353

[0676] [0676]

2 2

[0677] Smeša intermedijera 262 (310 mg, 0,61 mmol) u MeOH (5 ml) hidrogenovana je na sobnoj temperaturi (H2, atmosferski pritisak) sa Pd(OH)2 (20 mg) kao katalizatorom preko vikenda. Nakon preuzimanja H2(1 ekv.), smeša je filtrirana i filtrat je uparen radi dobijanja intermedijera 353 (260 mg, prinos 81,3%) koji je korišćen u sledećem koraku bez prečišćavanja. [0677] A mixture of intermediate 262 (310 mg, 0.61 mmol) in MeOH (5 mL) was hydrogenated at room temperature (H 2 , atmospheric pressure) with Pd(OH) 2 (20 mg) as catalyst over the weekend. After taking up H 2 (1 equiv), the mixture was filtered and the filtrate was evaporated to give intermediate 353 (260 mg, 81.3% yield) which was used in the next step without purification.

[0678] Sledeći intermedijeri su pripremljeni reakcionim protokolom koji je analogan protokolu korišćenom za pripremu intermedijera 353 koristeći odgovarajuće polazne supstance (Tabela 38). [0678] The following intermediates were prepared by a reaction protocol analogous to the protocol used for the preparation of intermediate 353 using the appropriate starting substances (Table 38).

Tabela 38: Table 38:

2 2

2 2

Primer A73 Example A73

Priprema intermedijera 403 Preparation of intermediates 403

[0679] [0679]

2 2

[0680] Smeša intermedijera 119 (600 mg, 0,82 mmol) i CH3NH2/EtOH (25 ml) u EtOH (25 ml) mešana je na 120°C preko noći u zaptivenoj epruveti. Reakciona smeša je koncentrovana radi dobijanja intermedijera 403 (600 mg) koji je korišćen u sledećem koraku bez daljeg prečišćavanja. [0680] A mixture of intermediate 119 (600 mg, 0.82 mmol) and CH 3 NH 2 /EtOH (25 mL) in EtOH (25 mL) was stirred at 120 °C overnight in a sealed tube. The reaction mixture was concentrated to give intermediate 403 (600 mg) which was used in the next step without further purification.

Primer A74 Example A74

Priprema intermedijera 404 Preparation of intermediates 404

[0681] [0681]

[0682] Intermedijer 228 (350 mg, 0,5 mmol) i metilamin (15 ml, 2 M) u EtOH mešani su na 120°C tokom 1,5 sati u mikrotalasnoj pećnici. Smeša je koncentrovana pod vakuumom radi dobijanja intermedijera 404 kao žute čvrste supstance. Sirovi proizvod je neposredno korišćen u sledećem koraku bez prečišćavanja. [0682] Intermediate 228 (350 mg, 0.5 mmol) and methylamine (15 mL, 2 M) in EtOH were stirred at 120 °C for 1.5 h in a microwave oven. The mixture was concentrated in vacuo to afford intermediate 404 as a yellow solid. The crude product was used directly in the next step without purification.

Primer A75 Example A75

Korak 1 Step 1

Priprema intermedijera 363 Preparation of intermediates 363

2 2

[0684] Smeša intermedijera 1 (250 mg, 0,77 mmol) i MeONa (331,5 mg, 6,14 mmol) u MeOH mešana je na sobnoj temperaturi tokom 1 h. Smeša je razblažena vodom (20 ml) i ekstrahovana je sa CH2Cl2(50 ml x 3). Organska faza je isprana zasićenim vodenim rastvorom soli (10 ml), osušena iznad Na2SO4, filtrirana i koncentrovana radi dobijanja intermedijera 363 (250 mg, prinos 96%) koji je korišćen u sledećem reakcionom koraku bez daljeg prečišćavanja. [0684] A mixture of intermediate 1 (250 mg, 0.77 mmol) and MeONa (331.5 mg, 6.14 mmol) in MeOH was stirred at room temperature for 1 h. The mixture was diluted with water (20 mL) and extracted with CH 2 Cl 2 (50 mL x 3). The organic phase was washed with brine (10 mL), dried over Na 2 SO 4 , filtered and concentrated to afford intermediate 363 (250 mg, 96% yield) which was used in the next reaction step without further purification.

Korak 2 Step 2

Priprema intermedijera 364 Preparation of intermediates 364

[0685] [0685]

[0686] TosCl (0,415 g, 2,18 mmol) ukapavanjem je dodat u smešu intermedijera 363 (0,35 g, 1,1 mmol), trietilamina (0,455 ml, 3,27 mmol) i 4-dimetilaminopiridina (67 mg, 0,545 mmol) u dihlormetanu (5 ml) uz hlađenje ledom. Smeša je mešana na sobnoj temperaturi tokom 3 h. Smeša je deaktivirana vodom (10 ml) i ekstrahovana je pomoću CH2Cl2(30 ml x 3). Organska faza je isprana zasićenim vodenim rastvorom soli (10 ml), osušena iznad Na2SO4, filtrirana i koncentrovana. Ostatak je zatim prečišćen hromatografijom na koloni (eluent: petrol etar/etil acetat odnos 1/0 do 3/1). Frakcije proizvoda su sakupljene, i rastvarač je uparen radi dobijanja intermedijera 364 (446 mg, prinos 86%) kao ulja. [0686] TosCl (0.415 g, 2.18 mmol) was added dropwise to a mixture of intermediate 363 (0.35 g, 1.1 mmol), triethylamine (0.455 mL, 3.27 mmol) and 4-dimethylaminopyridine (67 mg, 0.545 mmol) in dichloromethane (5 mL) under ice-cooling. The mixture was stirred at room temperature for 3 h. The mixture was quenched with water (10 mL) and extracted with CH 2 Cl 2 (30 mL x 3). The organic phase was washed with brine (10 mL), dried over Na 2 SO 4 , filtered and concentrated. The residue was then purified by column chromatography (eluent: petroleum ether/ethyl acetate ratio 1/0 to 3/1). The product fractions were collected, and the solvent was evaporated to give intermediate 364 (446 mg, 86% yield) as an oil.

Korak 3 Step 3

Priprema intermedijera 365 Preparation of intermediates 365

[0687] [0687]

[0688] Smeša intermedijera 364 (446 mg, 0,94 mmol), 2-amino-7-hidroksihinolina (167 mg, 1,04 mmol) i Cs2CO3(1,02 g, 3,13 mmol) u DMF-u (5 ml) mešana je na sobnoj temperaturi preko noći. Smeša je filtrirana i rastvarač je uparen. Ostatak je prečišćen hromatografijom na koloni (eluent: etil acetat). Frakcije proizvoda su sakupljene i rastvarač je uparen radi dobijanja intermedijera 365 (257,3 mg, prinos 53,3%) kao čvrste supstance. [0688] A mixture of intermediate 364 (446 mg, 0.94 mmol), 2-amino-7-hydroxyquinoline (167 mg, 1.04 mmol) and Cs 2 CO 3 (1.02 g, 3.13 mmol) in DMF (5 mL) was stirred at room temperature overnight. The mixture was filtered and the solvent was evaporated. The residue was purified by column chromatography (eluent: ethyl acetate). The product fractions were collected and the solvent was evaporated to give intermediate 365 (257.3 mg, 53.3% yield) as a solid.

Primer A76 Example A76

Priprema intermedijera 366 Preparation of intermediates 366

[0689] [0689]

[0690] Smeša intermedijera 306 (400 mg, 0,73 mmol) i MeONa (158,2 mg, 2,93 mmol) u MeOH (10 ml) mešana je na 60°C tokom 10 h. Smeša je razblažena vodom (20 ml), ekstrahovana sa CH2Cl2(50 ml x 3). Organska faza je isprana zasićenim vodenim rastvorom soli (10 ml), osušena iznad Na2SO4, filtrirana i koncentrovana radi dobijanja intermedijera 366 koji je korišćen u sledećem koraku bez daljeg prečišćavanja. [0690] A mixture of intermediate 306 (400 mg, 0.73 mmol) and MeONa (158.2 mg, 2.93 mmol) in MeOH (10 mL) was stirred at 60 °C for 10 h. The mixture was diluted with water (20 ml), extracted with CH 2 Cl 2 (50 ml x 3). The organic phase was washed with brine (10 mL), dried over Na 2 SO 4 , filtered and concentrated to afford intermediate 366 which was used in the next step without further purification.

1 1

[0691] Sledeći intermedijeri su pripremljeni reakcionim protokolom koji je analogan protokolu korišćenom za pripremu intermedijera 366 koristeći odgovarajuće polazne supstance (Tabela 39). [0691] The following intermediates were prepared by a reaction protocol analogous to the protocol used to prepare intermediate 366 using the appropriate starting substances (Table 39).

Tabela 39: Table 39:

2 2

Primer A76 Example A76

Priprema intermedijera 472 Preparation of intermediates 472

[0692] [0692]

[0693] Intermedijer 471 (900 mg, 1, 36 mmol) rastvoren je u TFA (3 ml). [0693] Intermediate 471 (900 mg, 1.36 mmol) was dissolved in TFA (3 mL).

[0694] Reakciona smeša je mešana na 50°C tokom 7 sati. [0694] The reaction mixture was stirred at 50°C for 7 hours.

[0695] Rastvarač je uparen radi dobijanja željenog intermedijera 472 kao ulja. [0695] The solvent was evaporated to give the desired intermediate 472 as an oil.

4 4

[0696] Sledeći intermedijeri su pripremljeni reakcionim protokolom koji je analogan protokolu koji je korišćen za pripremu intermedijera 472 koristeći odgovarajuće polazne supstance (Tabela 49). [0696] The following intermediates were prepared by a reaction protocol analogous to the protocol used to prepare intermediate 472 using the appropriate starting substances (Table 49).

Tabela 49: Table 49:

Primer A77 Example A77

Priprema intermedijera 376 Preparation of intermediates 376

[0697] [0697]

[0698] U intermedijer 264 (330 mg, 0,44 mmol) i C3H9B3O3(164 mg, 1,3 mmol) u dioksanu/H2O (6 ml, dioksan/H2O odnos 5/1,) dodat je K3PO4(277 mg, 1,3 mmol) i 1,1'-bis(diterc-butilfosfino)ferocen paladijum dihlorid (28,3 mg, 0,04 mmol). Smeša je mešana na 80°C preko noći. Smeša je tretirana vodom (30 ml) i ekstrahovana etil acetatom (40 ml x 3), osušena (Na2SO4), filtrirana i koncentrovana pod vakuumom radi dobijanja sirovog proizvoda kao smeđeg ulja. Sirovi proizvod je prečišćen fleš hromatografijom na koloni (elucioni gradijent: petrol etar:etil acetat od 20/1 do 3/1) radi dobijanja intermedijera 376 (170 mg, prinos 69%) kao žutog ulja. [0698] To intermediate 264 (330 mg, 0.44 mmol) and C3H9B3O3 (164 mg, 1.3 mmol) in dioxane/H2O (6 ml, dioxane/H2O ratio 5/1) was added K3PO4 (277 mg, 1.3 mmol) and 1,1'-bis(di-tert-butylphosphino)ferrocene palladium dichloride. (28.3 mg, 0.04 mmol). The mixture was stirred at 80°C overnight. The mixture was treated with water (30 mL) and extracted with ethyl acetate (40 mL x 3), dried (Na 2 SO 4 ), filtered and concentrated in vacuo to give the crude product as a brown oil. The crude product was purified by flash column chromatography (elution gradient: petroleum ether:ethyl acetate from 20/1 to 3/1) to give intermediate 376 (170 mg, 69% yield) as a yellow oil.

[0699] Sledeći intermedijeri su pripremljeni reakcionim protokolom koji je analogan protokolu korišćenom za pripremu intermedijera 376 koristeći odgovarajuće polazne supstance (Tabela 40). [0699] The following intermediates were prepared by a reaction protocol analogous to the protocol used to prepare intermediate 376 using the appropriate starting substances (Table 40).

Tabela 40: Table 40:

Primer A78 Example A78

Korak 1 Step 1

Priprema intermedijera 382 Preparation of intermediates 382

[0700] [0700]

[0701] U rastvor intermedijera 159 (0,85 g, 1,28 mmol) u dioksanu (20 ml) i H2O (5 ml) dodat je kalijum viniltrifluorborat (223 mg, 1,67 mmol) i trikalijum fosfat (544 mg, 2,57 mmol) na sobnoj temperaturi. U prethodni rastvor je dodat 1,1'-bis(di-terc-butilfosfino)ferocen paladijum dihlorid (42 mg, 0,064 mmol) u atmosferi azota. Reakciona smeša je mešana na 80°C u atmosferi azota preko noći. Smeša je ekstrahovana etil acetatom (20 ml x 2), organski slojevi su kombinovani i koncentrovani pod vakuumom. Ostatak je prečišćen hromatografijom na koloni (elucioni gradijent: etil acetat/petrol etar od 1/10 do 1/1). Željene frakcije su sakupljene i koncentrovane radi dobijanja proizvoda intermedijera 382 (400 mg, prinos: 60%) kao ulja. [0701] To a solution of intermediate 159 (0.85 g, 1.28 mmol) in dioxane (20 mL) and H2O (5 mL) was added potassium vinyltrifluoroborate (223 mg, 1.67 mmol) and tripotassium phosphate (544 mg, 2.57 mmol) at room temperature. To the previous solution was added 1,1'-bis(di-tert-butylphosphino)ferrocene palladium dichloride (42 mg, 0.064 mmol) under a nitrogen atmosphere. The reaction mixture was stirred at 80°C under nitrogen overnight. The mixture was extracted with ethyl acetate (20 mL x 2), the organic layers were combined and concentrated in vacuo. The residue was purified by column chromatography (elution gradient: ethyl acetate/petroleum ether from 1/10 to 1/1). The desired fractions were collected and concentrated to give the product intermediate 382 (400 mg, yield: 60%) as an oil.

Korak 2 Step 2

Priprema intermedijera 383 Preparation of intermediates 383

[0702] [0702]

[0703] Trifluorsirćetna kiselina (0,5 ml) dodata je u rastvor intermedijera 382 (400 mg, 0,78 mmol) u CH2Cl2(10 ml). Smeša je mešana na sobnoj temperaturi tokom 3 h. Smeša je uparena pod vakuumom radi dobijanja intermedijera 383 (300 mg, prinos: 48%). [0703] Trifluoroacetic acid (0.5 mL) was added to a solution of intermediate 382 (400 mg, 0.78 mmol) in CH 2 Cl 2 (10 mL). The mixture was stirred at room temperature for 3 h. The mixture was evaporated under vacuum to give intermediate 383 (300 mg, yield: 48%).

Primer A79 Example A79

Priprema intermedijera 384 i 385 Preparation of intermediates 384 and 385

[0704] [0704]

[0705] Me2NH (20 ml) dodat je u smešu intermedijera 262 (200 mg, 0,43 mmol) u dioksanu (20 ml) i mešan u zaptivenoj epruveti na 110°C preko noći. Reakciona smeša je koncentrovana radi dobijanja smeše intermedijera 384 i intermedijera 385 (210 mg) kao čvrste supstance. [0705] Me 2 NH (20 mL) was added to a mixture of intermediate 262 (200 mg, 0.43 mmol) in dioxane (20 mL) and stirred in a sealed tube at 110 °C overnight. The reaction mixture was concentrated to give a mixture of intermediate 384 and intermediate 385 (210 mg) as a solid.

Primer A80 Example A80

Korak 1 Step 1

Priprema intermedijera 412 Preparation of intermediates 412

[0706] [0706]

[0707] Smeša 2-amino-4-brom-benzaldehida (13 g, 65 mmol) i uree (54,6 g, 910 mmol) zagrevana je na 180°C u uljanom kupatilu tokom 2 sata. Reakcija je zatim ohlađena na sobnu temperaturu i dodat je H2O (500 ml). Reakciona smeša je mešana na sobnoj temperaturi tokom 1 sata. Čvrsta supstanca je sakupljena filtracijom radi dobijanja intermedijera 412 (16 g, prinos 93%) kao bele čvrste supstance. [0707] A mixture of 2-amino-4-bromo-benzaldehyde (13 g, 65 mmol) and urea (54.6 g, 910 mmol) was heated at 180°C in an oil bath for 2 hours. The reaction was then cooled to room temperature and H 2 O (500 mL) was added. The reaction mixture was stirred at room temperature for 1 hour. The solid was collected by filtration to afford intermediate 412 (16 g, 93% yield) as a white solid.

Korak 2 Step 2

Priprema intermedijera 413 Preparation of intermediates 413

[0708] [0708]

[0709] Smeša intermedijera 412 (16 g, 71 mmol) i POCl3(280 g, 1,84 mol) zagrejana je na 110°C u uljanom kupatilu u atmosferi N2tokom 3 sata. Reakcija je zatim ohlađena na sobnu temperaturu i sipana u led/vodu (4000 g). Reakciona smeša je mešana na sobnoj temperaturi tokom 1 sata i ekstrahovana je etil acetatom (2000 ml x 2). Organski sloj je ispran zasićenim vodenim rastvorom soli i osušen iznad anhidrovanog Na2SO4. Rastvarač je uparen pod vakuumom radi dobijanja sirovog proizvoda. Sirovi proizvod je prečišćen hromatografijom (etil acetat/petrol etar 0/1 do 1/5) radi dobijanja intermedijera 413 (10 g, prinos 53%) kao bele čvrste supstance. [0709] A mixture of intermediate 412 (16 g, 71 mmol) and POCl 3 (280 g, 1.84 mol) was heated to 110°C in an oil bath under N 2 atmosphere for 3 hours. The reaction was then cooled to room temperature and poured into ice/water (4000 g). The reaction mixture was stirred at room temperature for 1 hour and extracted with ethyl acetate (2000 ml x 2). The organic layer was washed with brine and dried over anhydrous Na2SO4. The solvent was evaporated under vacuum to give the crude product. The crude product was purified by chromatography (ethyl acetate/petroleum ether 0/1 to 1/5) to give intermediate 413 (10 g, 53% yield) as a white solid.

Korak 3 Step 3

Priprema intermedijera 386 Preparation of intermediates 386

[0710] [0710]

[0711] Smeša intermedijera 413 (4 g, 16,5 mmol), 4-metoksibenzilamina (3,4 g, 24,6 mmol) i cezijum karbonata (15 g, 49,3 mmol) u THF-u (100 ml) mešana je na sobnoj temperaturi tokom 12 sati. Reakciona smeša je filtrirana, i filtrat je uparen pod vakuumom radi dobijanja sirovog proizvoda. Sirovi proizvod je prečišćen hromatografijom (etil acetat/petrol etar 0/1 do 1/10) radi dobijanja intermedijera 386 (2,3 g, prinos 29%) kao ulja. [0711] A mixture of intermediate 413 (4 g, 16.5 mmol), 4-methoxybenzylamine (3.4 g, 24.6 mmol) and cesium carbonate (15 g, 49.3 mmol) in THF (100 mL) was stirred at room temperature for 12 h. The reaction mixture was filtered, and the filtrate was evaporated under vacuum to give the crude product. The crude product was purified by chromatography (ethyl acetate/petroleum ether 0/1 to 1/10) to give intermediate 386 (2.3 g, 29% yield) as an oil.

[0712] Sledeći intermedijeri su pripremljeni reakcionim protokolom koji je analogan protokolu korišćenom za pripremu intermedijera 386 koristeći odgovarajuće polazne supstance (Tabela 42). [0712] The following intermediates were prepared by a reaction protocol analogous to the protocol used to prepare intermediate 386 using the appropriate starting substances (Table 42).

Tabela 42: Table 42:

4 4

Korak 4 Step 4

Priprema intermedijera 387 Preparation of intermediates 387

[0713] [0713]

[0714] Intermedijer 38 (1,5 g, 4,69 mmol) u 9-BBN (0,5 M u THF-u, 56,3 ml, 28,1 mmol) refluktovan je tokom 1 h u atmosferi N2. Smeša je ohlađena na sobnu temperaturu, zatim je dodat K3PO4(2,98 g, 14,1 mmol) u H2O (5 ml), pa onda THF (40 ml), intermedijer 386 (2,1 g, 6,1 mmol) i Pd-118 (61,1 mg, 0,094 mmol). Dobijena smeša je refluktovana preko noći. Smeša je razblažena sa H2O (50 ml), ekstrahovana etil acetatom (150 ml), organska faza je osušena pomoću Na2SO4, zatim filtrirana i koncentrovana pod vakuumom radi dobijanja sirovog proizvoda. Sirovi proizvod je prečišćen hromatografijom (etil acetat/petrol etar 0/1 do 1/10) radi dobijanja intermedijera 387 (1,3 g, prinos: 47%) kao ulja. [0714] Intermediate 38 (1.5 g, 4.69 mmol) in 9-BBN (0.5 M in THF, 56.3 ml, 28.1 mmol) was refluxed for 1 h under N 2 . The mixture was cooled to room temperature, then K 3 PO 4 (2.98 g, 14.1 mmol) in H 2 O (5 mL) was added, followed by THF (40 mL), intermediate 386 (2.1 g, 6.1 mmol) and Pd-118 (61.1 mg, 0.094 mmol). The resulting mixture was refluxed overnight. The mixture was diluted with H 2 O (50 ml), extracted with ethyl acetate (150 ml), the organic phase was dried over Na 2 SO 4 , then filtered and concentrated in vacuo to give the crude product. The crude product was purified by chromatography (ethyl acetate/petroleum ether 0/1 to 1/10) to give intermediate 387 (1.3 g, yield: 47%) as an oil.

Korak 5 Step 5

Priprema intermedijera 388 Preparation of intermediates 388

[0715] [0715]

41 41

[0716] Intermedijer 387 (500 mg, 0,85 mmol) rastvoren je u TFA (10 ml) i mešan na 60°C tokom 1 sata. Smeša je koncentrovana radi dobijanja sirovog intermedijera 388 (1 g kao čvrste supstance. [0716] Intermediate 387 (500 mg, 0.85 mmol) was dissolved in TFA (10 ml) and stirred at 60°C for 1 hour. The mixture was concentrated to give crude intermediate 388 (1 g as a solid.

Primer A81 Example A81

Korak 1 Step 1

Priprema intermedijera 389 Preparation of intermediates 389

[0717] [0717]

[0718] Smeša intermedijera 387 (450 mg, 0,77 mmol) i NH3.H2O (10 ml) u dioksanu (10 ml) zagrevana je na 80°C tokom 24 sata u zaptivenoj epruveti. Reakciona smeša je ekstrahovana etil acetatom (50 ml x 3). Organski slojevi su razdvojeni, osušeni iznad Na2SO4i rastvarač je uparen radi dobijanja intermedijera 389 (290 mg, prinos 66,6%) kao ulja. [0718] A mixture of intermediate 387 (450 mg, 0.77 mmol) and NH 3 .H 2 O (10 ml) in dioxane (10 ml) was heated at 80 °C for 24 hours in a sealed tube. The reaction mixture was extracted with ethyl acetate (50 ml x 3). The organic layers were separated, dried over Na 2 SO 4 and the solvent was evaporated to give intermediate 389 (290 mg, 66.6% yield) as an oil.

Korak 2 Step 2

Priprema intermedijera 390 Preparation of intermediates 390

[0719] [0719]

42 42

[0720] Intermedijer 389 (290 mg, 0,51 mmol) rastvoren je u TFA (10 ml) i mešan na 60°C tokom 1 sata. Smeša je koncentrovana radi dobijanja sirovog intermedijera 390 (300 mg) kao ulja. [0720] Intermediate 389 (290 mg, 0.51 mmol) was dissolved in TFA (10 ml) and stirred at 60°C for 1 hour. The mixture was concentrated to give crude intermediate 390 (300 mg) as an oil.

Primer A82 Example A82

Priprema intermedijera 347 Preparation of intermediates 347

[0721] [0721]

[0722] Smeša intermedijera 327 (1100 mg, 2,20 mmol) u metilaminu/etanolu (30 ml, 40%) zagrevana je u zaptivenoj epruveti na 80°C tokom 24 h. Organska faza je koncentrovana radi dobijanja intermedijera 347 (1,2 g, prinos 99%) [0722] A mixture of intermediate 327 (1100 mg, 2.20 mmol) in methylamine/ethanol (30 mL, 40%) was heated in a sealed tube at 80°C for 24 h. The organic phase was concentrated to give intermediate 347 (1.2 g, yield 99%)

Primer A83 Example A83

Priprema intermedijera 372 Preparation of intermediates 372

[0723] [0723]

[0724] Smeša intermedijera 327 (550 mg, 1,1 mmol), natrijum metoksida (356,3 mg, 6,60 mmol) u metanolu (10 ml) refluktovana je na 60°C tokom 12 h. Reakciona smeša je uparena [0724] A mixture of intermediate 327 (550 mg, 1.1 mmol), sodium methoxide (356.3 mg, 6.60 mmol) in methanol (10 mL) was refluxed at 60°C for 12 h. The reaction mixture was evaporated

4 4

pod vakuumom. Dodata je voda (10 ml) i smeša je ekstrahovana etil acetatom (10 ml x 2), organski slojevi su kombinovani i upareni pod vakuumom radi dobijanja intermedijera 372 (510 mg, prinos 75%) kao ulja. under vacuum. Water (10 mL) was added and the mixture was extracted with ethyl acetate (10 mL x 2), the organic layers were combined and evaporated in vacuo to afford intermediate 372 (510 mg, 75% yield) as an oil.

Primer A84 Example A84

Korak 1 Step 1

Priprema intermedijera 393 Preparation of intermediates 393

[0725] [0725]

[0726] 7-brom-3-(trifluormetil)hinolin) (1,0 g, 3,62 mmol) rastvoren je u DCM-u (30 ml), m-CPBA (1,25 g, 7,25 mmol) je u porcijama dodat u smešu. Dobijena smeša je mešana na sobnoj temperaturi preko noći. Reakciona smeša je sipana u smešu zasićenog Na2S2O3(50,0 ml) i 1 N vodenog rastvora NaOH (50 ml). Smeša je zatim ekstrahovana DCM-om (200 ml x 2), i kombinovane organske faze su isprane zasićenim vodenim rastvorom soli (100 ml), osušene iznad anhidrovanog Na2SO4, filtrirane i koncentrovane radi dobijanja proizvoda intermedijera 393 (1,0 g, prinos 80%) kao smeđe čvrste supstance koja je korišćena u sledećem koraku bez daljeg prečišćavanja. [0726] 7-Bromo-3-(trifluoromethyl)quinoline) (1.0 g, 3.62 mmol) was dissolved in DCM (30 mL), m-CPBA (1.25 g, 7.25 mmol) was added portionwise to the mixture. The resulting mixture was stirred at room temperature overnight. The reaction mixture was poured into a mixture of saturated Na2S2O3 (50.0 ml) and 1 N aqueous NaOH solution (50 ml). The mixture was then extracted with DCM (200 ml x 2), and the combined organic phases were washed with brine (100 ml), dried over anhydrous Na 2 SO 4 , filtered and concentrated to give the product intermediate 393 (1.0 g, 80% yield) as a brown solid which was used in the next step without further purification.

Korak 2 Step 2

Priprema intermedijera 394 Preparation of intermediates 394

[0727] [0727]

44 44

[0728] Intermedijer 393 (200 mg, 0,685 mmol) prenet je u CHCl3(10 ml). Na sobnoj temperaturi je dodat POCl3(1,0 ml). Reakciona smeša je mešana na 80°C tokom 12 sati. Rastvarač je uklonjen pod sniženim pritiskom, ostatak je trituriran pomoću etil acetata (50 ml) i zas. Na2CO3(50 ml), organski sloj je razdvojen, organski sloj je ispran zasićenim vodenim rastvorom soli (50 ml) i osušen iznad anhidrovanog Na2SO4. Rastvarač je uklonjen pod sniženim pritiskom radi dobijanja intermedijera 394 (200 mg, 83%) kao smeđeg ulja. [0728] Intermediate 393 (200 mg, 0.685 mmol) was taken up in CHCl 3 (10 mL). POCl3 (1.0 ml) was added at room temperature. The reaction mixture was stirred at 80°C for 12 hours. The solvent was removed under reduced pressure, the residue was triturated with ethyl acetate (50 ml) and sat. Na 2 CO 3 (50 ml), the organic layer was separated, the organic layer was washed with brine (50 ml) and dried over anhydrous Na 2 SO 4 . The solvent was removed under reduced pressure to afford intermediate 394 (200 mg, 83%) as a brown oil.

Korak 3 Step 3

Priprema intermedijera 314 Preparation of intermediates 314

[0729] [0729]

[0730] Intermedijer 394 (2,2 g, 5,43 mmol) rastvoren je u dioksanu (30 ml) i dodat je NH3H2O (30 ml). Reakciona smeša je mešana na 120°C u autoklavu preko noći. Rastvarač je uklonjen pod sniženim pritiskom, ostatak je prečišćen hromatografijom na koloni (EtOAc/petrol etar odnos: 0/10 do 1/10) radi dobijanja intermedijera 314 (1,4 g, prinos 88,6%) kao bele čvrste supstance. [0730] Intermediate 394 (2.2 g, 5.43 mmol) was dissolved in dioxane (30 mL) and NH 3 H 2 O (30 mL) was added. The reaction mixture was stirred at 120°C in an autoclave overnight. The solvent was removed under reduced pressure, the residue was purified by column chromatography (EtOAc/petroleum ether ratio: 0/10 to 1/10) to give intermediate 314 (1.4 g, yield 88.6%) as a white solid.

Primer A85 Example A85

Priprema intermedijera 348 Preparation of intermediates 348

[0731] [0731]

4 4

[0732] Intermedijer 315 (420 mg, 0,79 mmol) rastvoren je u etanolnom rastvoru MeNH2(30%, 30 ml) i EtOH (30 ml). Reakciona smeša je mešana na 100°C u autoklavu tokom 12 sati. Rastvarač je uklonjen pod sniženim pritiskom radi dobijanja intermedijera 348 (450 mg, sirov) kao smeđe čvrste supstance koja je korišćena u sledećem koraku bez daljeg prečišćavanja. [0732] Intermediate 315 (420 mg, 0.79 mmol) was dissolved in an ethanol solution of MeNH 2 (30%, 30 ml) and EtOH (30 ml). The reaction mixture was stirred at 100°C in an autoclave for 12 hours. The solvent was removed under reduced pressure to afford intermediate 348 (450 mg, crude) as a brown solid which was used in the next step without further purification.

Primer A86 Example A86

Korak 1 Step 1

Priprema intermedijera 373 Preparation of intermediates 373

[0733] [0733]

[0734] Intermedijer 315 (300 mg, 0,56 mmol) rastvoren je u MeOH (20 ml), dodat je MeONa (483 mg, 4,46 mmol). Reakciona smeša je mešana na 70°C tokom 12 sati. Rastvarač je uklonjen pod sniženim pritiskom radi dobijanja intermedijera 373 (340 mg, sirov) kao smeđe čvrste supstance koja je korišćena u sledećem koraku bez daljeg prečišćavanja. [0734] Intermediate 315 (300 mg, 0.56 mmol) was dissolved in MeOH (20 mL), MeONa (483 mg, 4.46 mmol) was added. The reaction mixture was stirred at 70°C for 12 hours. The solvent was removed under reduced pressure to afford intermediate 373 (340 mg, crude) as a brown solid which was used in the next step without further purification.

Primer A87 Example A87

Korak 1 Step 1

4 4

Priprema intermedijera 395 Preparation of intermediates 395

[0735] [0735]

[0736] 1H-izoindol-1,3(2H)-dion, kalijumova so (1:1) (50 g, 221,9 mmol) i 2-brom-1,1-dietoksi-etan (54,7 g, 277,4 mmol) u DMF-u mešani su na 150°C tokom 4 sata. DMF je uklonjen pod sniženim pritiskom. Ostatak je prečišćen hromatografijom na koloni (eluent: petrol etar/etil acetat odnos 5/1) radi dobijanja intermedijera 395 (40 g, prinos: 64%) kao bele čvrste supstance. [0736] 1H-isoindole-1,3(2H)-dione, potassium salt (1:1) (50 g, 221.9 mmol) and 2-bromo-1,1-diethoxy-ethane (54.7 g, 277.4 mmol) in DMF were stirred at 150°C for 4 hours. DMF was removed under reduced pressure. The residue was purified by column chromatography (eluent: petroleum ether/ethyl acetate ratio 5/1) to give intermediate 395 (40 g, yield: 64%) as a white solid.

Korak 2 Step 2

Priprema intermedijera 396 Preparation of intermediates 396

[0737] [0737]

[0738] Smeša intermedijera 395 (22,1 g, 84,0 mmol), 4-brom-2-amino-benzaldehida (14 g, 70,0 mmol) i p-MeC6H4SO3H.H2O (13,3 g, 70,0 mmol) u PhMe (200 ml) refluktovana je tokom 4 sata. Smeša je ohlađena i filtrirana. Čvrsta supstanca je isprana toluenom radi dobijanja sirove PTSA soli proizvoda kao smeđe čvrste supstance. Čvrsta supstanca je mešana u zasićenom vod. natrijum bikarbonatu i ekstrahovana dihlormetanom. Rastvarač je uparen, i preostala čvrsta [0738] A mixture of intermediate 395 (22.1 g, 84.0 mmol), 4-bromo-2-amino-benzaldehyde (14 g, 70.0 mmol) and p-MeC6H4SO3H.H2O (13.3 g, 70.0 mmol) in PhMe (200 mL) was refluxed for 4 h. The mixture was cooled and filtered. The solid was washed with toluene to give the crude PTSA salt of the product as a brown solid. The solid is mixed in saturated water. sodium bicarbonate and extracted with dichloromethane. The solvent was evaporated, and a solid remained

4 4

supstanca je suspendovana u etanolu i sakupljena radi dobijanja intermedijera 396 (14,2 g, prinos 56%). the substance was suspended in ethanol and collected to give intermediate 396 (14.2 g, 56% yield).

Korak 3 Step 3

Priprema intermedijera 397 Preparation of intermediates 397

[0739] [0739]

[0740] Suspenzija intermedijera 396 (14 g, 38,5 mmol) u etanolu (150 ml) tretirana je sa NH2NH2.H2O (4,5 g, 76,9 mmol) i refluktovana je tokom 1 sata. Smeša je ostavljena da se ohladi i filtrirana. Filtrat je sakupljen i uparen radi dobijanja intermedijera 397 (8,6 g, prinos 94%). [0740] A suspension of intermediate 396 (14 g, 38.5 mmol) in ethanol (150 mL) was treated with NH 2 NH 2 .H 2 O (4.5 g, 76.9 mmol) and refluxed for 1 hour. The mixture was allowed to cool and filtered. The filtrate was collected and evaporated to give intermediate 397 (8.6 g, 94% yield).

Korak 4 Step 4

Priprema intermedijera 398 Preparation of intermediates 398

[0741] [0741]

[0742] Intermedijer 397 (8 g, 35,86 mmol) rastvoren je u PhCl (80 ml). Ukapavanjem je dodat bor trifluorid dietil eterat (4,45 ml) tokom 10 min. Smeša je zagrejana na 60°C. Dodat je tercbutil nitrit (6,1 ml) ukapavanjem tokom 20 min na toj temperaturi. Reakcioni rastvor je zagrejan na 100°C i mešan tokom 1 sata. Smeša je ohlađena i sipana u led/vodeni rastvor natrijum bikarbonata. Smeša je ekstrahovana pomoću CH2Cl2(500 ml x 2). Kombinovani [0742] Intermediate 397 (8 g, 35.86 mmol) was dissolved in PhCl (80 mL). Boron trifluoride diethyl etherate (4.45 ml) was added dropwise over 10 min. The mixture was heated to 60°C. Tert-butyl nitrite (6.1 mL) was added dropwise over 20 min at that temperature. The reaction solution was heated to 100°C and stirred for 1 hour. The mixture was cooled and poured into an ice/aqueous sodium bicarbonate solution. The mixture was extracted with CH 2 Cl 2 (500 ml x 2). Combined

4 4

organski slojevi su isprani zasićenim vodenim rastvorom soli, osušeni (Na2SO4) i koncentrovani pod vakuumom radi dobijanja sirovog proizvoda. Sirovi proizvod je prečišćen hromatografijom na koloni (elucioni gradijent: petrol etar/etil acetat od 1/0 do 20/1) radi dobijanja intermedijera 398 (1,57 g, prinos 19%). the organic layers were washed with brine, dried (Na 2 SO 4 ) and concentrated in vacuo to give the crude product. The crude product was purified by column chromatography (elution gradient: petroleum ether/ethyl acetate from 1/0 to 20/1) to give intermediate 398 (1.57 g, 19% yield).

Korak 5 Step 5

[0743] Priprema intermedijera 399 [0743] Preparation of Intermediate 399

[0744] Smeša intermedijera 398 (1,57 g, 6,95 mmol) i m-CPBA (2,1 g, 10,4 mmol) u CHCl3(30 ml) mešana je na 50°C preko noći. Reakcioni rastvor je deaktiviran rastvorom Na2SO3(50 ml) i zalužen rastvorom NaHCO3(50 ml). Smeša je ekstrahovana pomoću CH2Cl2(300 ml x 3). Kombinovani organski slojevi su isprani zasićenim vodenim rastvorom soli, osušeni (Na2SO4), filtrirani i koncentrovani pod vakuumom radi dobijanja intermedijera 399 (2 g, prinos 97,2%) kao smeđe čvrste supstance. [0744] A mixture of intermediate 398 (1.57 g, 6.95 mmol) and m-CPBA (2.1 g, 10.4 mmol) in CHCl 3 (30 mL) was stirred at 50 °C overnight. The reaction solution was deactivated with Na2SO3 solution (50 ml) and alkalized with NaHCO3 solution (50 ml). The mixture was extracted with CH 2 Cl 2 (300 mL x 3). The combined organic layers were washed with brine, dried (Na 2 SO 4 ), filtered and concentrated in vacuo to afford intermediate 399 (2 g, 97.2% yield) as a brown solid.

Korak 6 Step 6

Priprema intermedijera 400 Preparation of intermediate 400

[0745] [0745]

[0746] Smeša intermedijera 399 (2 g, 6,75 mmol) i POCl3(10,6 g, 69 mmol) u CHCl3(40 ml) refluktovana je tokom 3 sata. Reakcioni rastvor je sipan u vodu (100 ml), zalužen rastvorom NaHCO3(80 ml) do pH > 7 i mešan tokom 5 min. Smeša je ekstrahovana pomoću DCM (500 ml x 3). Kombinovani organski slojevi su isprani zasićenim vodenim rastvorom soli, osušeni [0746] A mixture of intermediate 399 (2 g, 6.75 mmol) and POCl 3 (10.6 g, 69 mmol) in CHCl 3 (40 mL) was refluxed for 3 hours. The reaction solution was poured into water (100 ml), basified with NaHCO3 solution (80 ml) until pH > 7 and stirred for 5 min. The mixture was extracted with DCM (500 ml x 3). The combined organic layers were washed with saturated aqueous salt solution, dried

4 4

(Na2SO4), filtrirani i koncentrovani pod vakuumom radi dobijanja sirovog proizvoda kao žute čvrste supstance. Sirovi proizvod je prečišćen hromatografijom na koloni silika gela (petrol etar/etil acetat: odnos 1/0 do petrol etar/etil acetat 10/1). Čiste frakcije su sakupljene, i rastvarač je uparen pod vakuumom radi dobijanja intermedijera 400 (1,4 mg, prinos 78%) kao bele čvrste supstance. (Na2SO4), filtered and concentrated under vacuum to give the crude product as a yellow solid. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate: ratio 1/0 to petroleum ether/ethyl acetate 10/1). Pure fractions were collected, and the solvent was evaporated under vacuum to give intermediate 400 (1.4 mg, 78% yield) as a white solid.

Korak 7 Step 7

Priprema intermedijera 329 Preparation of intermediates 329

[0747] [0747]

[0748] Smeša intermedijera 400 (600 mg, 2,3 mmol) i NH3·H2O (15 ml) u CH3CH2OH (15 ml) zagrevana je u zaptivenoj epruveti na 120°C preko noći. Smeša je koncentrovana pod vakuumom. Ostatak je prečišćen hromatografijom na koloni silika gela (petrol etar/etil acetat od 20/1 do petrol etar/etil acetat 1/1). Čiste frakcije su sakupljene i rastvarač je uparen pod vakuumom radi dobijanja intermedijera 329 (390 mg, prinos 67%) kao bele čvrste supstance. [0748] A mixture of intermediate 400 (600 mg, 2.3 mmol) and NH 3 ·H 2 O (15 ml) in CH 3 CH 2 OH (15 ml) was heated in a sealed tube at 120 °C overnight. The mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate from 20/1 to petroleum ether/ethyl acetate 1/1). Pure fractions were collected and the solvent was evaporated under vacuum to give intermediate 329 (390 mg, 67% yield) as a white solid.

Primer A88 Example A88

Korak 1 Step 1

Priprema intermedijera 330 Preparation of intermediates 330

[0749] [0749]

[0750] Intermedijer 38 (470 mg, 1,47 mmol) u 9-BBN (0,5 M u THF-u, 11,8 ml, 5,9 mmol) refluktovan je tokom 1 h u atmosferi N2. Smeša je ohlađena na sobnu temperaturu, zatim je dodat K3PO4(936,6 mg, 4,41 mmol) u H2O (2 ml), pa onda THF (20 ml), intermedijer 329 (390 mg, 1,62 mmol) i Pd-118 (19,2 mg, 0,029 mmol). Dobijena smeša je refluktovana preko noći. Smeša je razblažena pomoću H2O (80 ml) i ekstrahovana etil acetatom (150 ml). Organska faza je osušena sa Na2SO4, zatim filtrirana i koncentrovana pod vakuumom radi dobijanja sirovog proizvoda. Sirovi proizvod je prečišćen hromatografijom (etil acetat/petrol etar od 0/1 do 1/3) radi dobijanja intermedijera 330 (460 mg, prinos 55%) kao žutog ulja. [0750] Intermediate 38 (470 mg, 1.47 mmol) in 9-BBN (0.5 M in THF, 11.8 mL, 5.9 mmol) was refluxed for 1 h under N 2 . The mixture was cooled to room temperature, then K3PO4 (936.6 mg, 4.41 mmol) in H2O (2 mL) was added, followed by THF (20 mL), intermediate 329 (390 mg, 1.62 mmol), and Pd-118 (19.2 mg, 0.029 mmol). The resulting mixture was refluxed overnight. The mixture was diluted with H 2 O (80 mL) and extracted with ethyl acetate (150 mL). The organic phase was dried with Na2SO4, then filtered and concentrated under vacuum to give the crude product. The crude product was purified by chromatography (ethyl acetate/petroleum ether 0/1 to 1/3) to give intermediate 330 (460 mg, 55% yield) as a yellow oil.

Korak 2 Step 2

Priprema intermedijera 374 Preparation of intermediates 374

[0751] [0751]

[0752] Smeša intermedijera 330 (400 mg, 0,70 mmol) i CH3ONa (380,17 mg, 7,04 mmol) u CH3OH (15 ml) refluktovana je preko noći. Smeša je koncentrovana pod vakuumom. Ostatak je tretiran vodom (60 ml) i ekstrahovan pomoću EtOAc (100 ml x 3). Kombinovani organski slojevi su isprani zasićenim vodenim rastvorom soli, osušeni (Na2SO4), filtrirani i koncentrovani pod sniženim pritiskom radi dobijanja intermedijera 374 (350 mg, prinos 87%) kao smeđeg ulja. [0752] A mixture of intermediate 330 (400 mg, 0.70 mmol) and CH 3 ONa (380.17 mg, 7.04 mmol) in CH 3 OH (15 mL) was refluxed overnight. The mixture was concentrated under vacuum. The residue was treated with water (60 mL) and extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine, dried (Na 2 SO 4 ), filtered and concentrated under reduced pressure to afford intermediate 374 (350 mg, 87% yield) as a brown oil.

Primer A89 Example A89

Korak 1 Step 1

Priprema intermedijera 323 Preparation of intermediates 323

1 1

[0754] Rastvor intermedijera 400 (400 mg, 1,54 mmol) u CH3NH2(40% rastvor u 20 ml CH3CH2OH) zagrevan je u zaptivenoj epruveti na 120°C preko noći. Smeša je koncentrovana pod vakuumom. Sirovi proizvod je prečišćen hromatografijom na koloni (elucioni gradijent: petrol etar/etil acetat od 20/1 do 5/1) radi dobijanja intermedijera 323 (350 mg, prinos 89%) kao žute čvrste supstance. [0754] A solution of Intermediate 400 (400 mg, 1.54 mmol) in CH 3 NH 2 (40% solution in 20 ml CH 3 CH 2 OH) was heated in a sealed tube at 120 °C overnight. The mixture was concentrated under vacuum. The crude product was purified by column chromatography (elution gradient: petroleum ether/ethyl acetate from 20/1 to 5/1) to give intermediate 323 (350 mg, 89% yield) as a yellow solid.

Korak 2 Step 2

Priprema intermedijera 324 Preparation of intermediates 324

[0755] [0755]

[0756] Intermedijer 38 (365 mg, 1,14 mmol) u 9-BBN (0,5 mol/l u THF-u, 11,4 ml, 5,72 mmol) refluktovan je tokom 1 h u atmosferi N2. Smeša je ohlađena na sobnu temperaturu, zatim je dodat K3PO4(728 mg, 3,43 mmol) u H2O (2 ml), pa onda THF (20 ml), intermedijer 323 (350 mg, 1,37 mmol) i Pd-118 (14,90 mg, 0,023 mmol). Dobijena smeša je refluktovana preko noći. Smeša je razblažena pomoću H2O (80 ml) i ekstrahovana etil acetatom (100 ml). Organska faza je osušena pomoću Na2SO4, filtrirana i koncentrovana pod vakuumom radi dobijanja sirovog proizvoda. Sirovi proizvod je prečišćen hromatografijom (etil acetat/petrol etar od 1/10 do 1/5) radi dobijanja intermedijera 324 (350 mg, prinos 61%) kao žutog ulja. [0756] Intermediate 38 (365 mg, 1.14 mmol) in 9-BBN (0.5 mol/l in THF, 11.4 ml, 5.72 mmol) was refluxed for 1 h under N 2 . The mixture was cooled to room temperature, then K3PO4 (728 mg, 3.43 mmol) in H2O (2 mL) was added, followed by THF (20 mL), intermediate 323 (350 mg, 1.37 mmol), and Pd-118 (14.90 mg, 0.023 mmol). The resulting mixture was refluxed overnight. The mixture was diluted with H 2 O (80 mL) and extracted with ethyl acetate (100 mL). The organic phase was dried over Na2SO4, filtered and concentrated under vacuum to give the crude product. The crude product was purified by chromatography (ethyl acetate/petroleum ether 1/10 to 1/5) to give intermediate 324 (350 mg, 61% yield) as a yellow oil.

2 2

Korak 3 Step 3

Priprema intermedijera 350 Preparation of intermediate 350

[0757] [0757]

[0758] Rastvor intermedijera 324 (350 mg, 0,71 mmol) u CH3NH2(40% rastvor u 10 ml EtOH) zagrevan je u zaptivenoj epruveti na 120°C preko noći. Smeša je koncentrovana pod vakuumom radi dobijanja intermedijera 350 (350 mg, prinos 97%). [0758] A solution of intermediate 324 (350 mg, 0.71 mmol) in CH 3 NH 2 (40% solution in 10 ml EtOH) was heated in a sealed tube at 120 °C overnight. The mixture was concentrated under vacuum to give intermediate 350 (350 mg, 97% yield).

Primer A90 Example A90

Priprema intermedijera 349 Preparation of intermediates 349

[0759] [0759]

[0760] Rastvor intermedijera 330 (350 mg, 0,726 mmol) u CH3NH2(40% rastvor u 15 ml CH3CH2OH) zagrevan je u zaptivenoj epruveti na 120°C preko noći. Smeša je koncentrovana pod vakuumom radi dobijanja intermedijera 349 (350 mg, prinos 99,9%). [0760] A solution of intermediate 330 (350 mg, 0.726 mmol) in CH 3 NH 2 (40% solution in 15 ml CH 3 CH 2 OH) was heated in a sealed tube at 120 °C overnight. The mixture was concentrated under vacuum to give intermediate 349 (350 mg, 99.9% yield).

Primer A91 Example A91

Korak 1 Step 1

Priprema intermedijera 414 Preparation of intermediates 414

[0761] [0761]

[0762] U rastvor intermedijera 1 (1,0 g, 4,9 mmol), 7-hidroksihinolin-2-metilkarboksilata (1,36 g, 4,18 mmol) i PPh3(2,58 g, 9,84 mmol) u THF-u (10 ml) dodat je DIAD (1,99 g, 9,84 mmol) na 0°C. Smeša je mešana na sobnoj temperaturi preko noći u atmosferi N2. Dodata je voda (25 ml) i smeša je ekstrahovana etil acetatom (100 ml x 3). Kombinovani organski slojevi su isprani zasićenim vodenim rastvorom soli (1000 ml). Organska faza je osušena iznad anhidrovanog Na2SO4, filtrirana i koncentrovana radi dobijanja sirovog proizvoda kao ulja. Sirovi proizvod je prečišćen hromatografijom na koloni silika gela (elucija: petrol etar/etil acetat odnos 1/1). Željene frakcije su sakupljene i koncentrovane radi dobijanja proizvoda intermedijera 414 (1,2 g, prinos 31%) kao čvrste supstance. [0762] To a solution of intermediate 1 (1.0 g, 4.9 mmol), 7-hydroxyquinoline-2-methylcarboxylate (1.36 g, 4.18 mmol) and PPh3 (2.58 g, 9.84 mmol) in THF (10 ml) was added DIAD (1.99 g, 9.84 mmol) at 0°C. The mixture was stirred at room temperature overnight under a N2 atmosphere. Water (25 mL) was added and the mixture was extracted with ethyl acetate (100 mL x 3). The combined organic layers were washed with brine (1000 mL). The organic phase was dried over anhydrous Na 2 SO 4 , filtered and concentrated to give the crude product as an oil. The crude product was purified by silica gel column chromatography (elution: petroleum ether/ethyl acetate ratio 1/1). The desired fractions were collected and concentrated to give the product intermediate 414 (1.2 g, 31% yield) as a solid.

Korak 2 Step 2

Priprema intermedijera 415 Preparation of intermediates 415

[0763] [0763]

4 4

[0764] U rastvor intermedijera 414 (600 mg, 1,18 mmol) u EtOH (5 ml) dodat je NaBH4(0,132 g, 3,53 mmol) na sobnoj temperaturi u atmosferi N2. Reakciona smeša je mešana na sobnoj temperaturi tokom 3 sata. Dodata je voda (20 ml) i smeša je ekstrahovana pomoću CH2Cl2(50 ml x 3). Organski slojevi su kombinovani, osušeni (Na2SO4), filtrirani i koncentrovani radi dobijanja željenog proizvoda kao ulja. Sirovi proizvod je prečišćen hromatografijom na koloni silika gela (eluent: etil acetat). Željene frakcije su koncentrovane radi dobijanja intermedijera 415 (0,27 g, prinos 54,3%) kao čvrste supstance. [0764] To a solution of intermediate 414 (600 mg, 1.18 mmol) in EtOH (5 mL) was added NaBH 4 (0.132 g, 3.53 mmol) at room temperature under N 2 . The reaction mixture was stirred at room temperature for 3 hours. Water (20 mL) was added and the mixture was extracted with CH 2 Cl 2 (50 mL x 3). The organic layers were combined, dried (Na2SO4), filtered and concentrated to give the desired product as an oil. The crude product was purified by silica gel column chromatography (eluent: ethyl acetate). The desired fractions were concentrated to give intermediate 415 (0.27 g, 54.3% yield) as a solid.

Korak 3 Step 3

Priprema intermedijera 416 Preparation of intermediates 416

[0765] [0765]

[0766] U rastvor intermedijera 415 (0,27 g, 0,56 mmol) u anhidrovanom DMF-u (5 ml) dodat je 60% NaH (33,5 mg, 0,83 mmol). Reakciona smeša je mešana na sobnoj temperaturi tokom 20 min u atmosferi argona. Ukapavanjem je zatim dodat MeI (158 ml, 1,12 mmol). Reakciona smeša je mešana na sobnoj temperaturi tokom 1 h. Smeša je sipana u ledenu vodu (10 ml) i ekstrahovana pomoću CH2Cl2(40 ml x 3). Kombinovani ekstrakti su isprani zasićenim vodenim rastvorom soli, osušeni iznad Na2SO4, filtrirani i upareni radi dobijanja proizvoda kao ulja. Sirovi proizvod je prečišćen na koloni (eluent: petrol etar/etil acetat 20/1 od 1/1) radi dobijanja intermedijera 416 (120 mg, prinos 43%) kao čvrste supstance. [0766] To a solution of intermediate 415 (0.27 g, 0.56 mmol) in anhydrous DMF (5 mL) was added 60% NaH (33.5 mg, 0.83 mmol). The reaction mixture was stirred at room temperature for 20 min under an argon atmosphere. MeI (158 mL, 1.12 mmol) was then added dropwise. The reaction mixture was stirred at room temperature for 1 h. The mixture was poured into ice water (10 mL) and extracted with CH 2 Cl 2 (40 mL x 3). The combined extracts were washed with brine, dried over Na 2 SO 4 , filtered and evaporated to give the product as an oil. The crude product was purified on a column (eluent: petroleum ether/ethyl acetate 20/1 of 1/1) to give intermediate 416 (120 mg, 43% yield) as a solid.

Korak 4 Step 4

Priprema intermedijera 417 Preparation of intermediates 417

[0767] [0767]

[0768] Rastvor intermedijera 416 (120 mg, 0,24 mmol) u NH3.H2O (5 ml) i dioksanu (5 ml) mešan je u zaptivenoj epruveti. Smeša je mešana na 90°C preko noći. Reakcija je koncentrovana radi dobijanja sirovog proizvoda kao ulja. Sirovi proizvod je prečišćen pomoću prep-TLC (DCM/MeOH: odnos 10/1) radi dobijanja intermedijera 417 (70 mg, prinos 44%) kao čvrste supstance. [0768] A solution of intermediate 416 (120 mg, 0.24 mmol) in NH 3 .H 2 O (5 ml) and dioxane (5 ml) was mixed in a sealed tube. The mixture was stirred at 90°C overnight. The reaction was concentrated to give the crude product as an oil. The crude product was purified by prep-TLC (DCM/MeOH: 10/1 ratio) to afford intermediate 417 (70 mg, 44% yield) as a solid.

Primer A92 Example A92

Korak 1 Step 1

Priprema intermedijera 418 Preparation of intermediates 418

[0769] [0769]

[0770] U rastvor adenozina (75 g, 281 mmol) u acetonu (1200 ml) i DMF-u (400 ml) dodat je 2,2-dimetoksipropan (35,1 g, 336,8 mmol) i metansulfonska kiselina (40,5 g, 421 mmol) u atmosferi N2. Reakciona smeša je mešana na 60°C tokom 6 h. Reakciona smeša je tretirana vodenim NaHCO3(pH do 7-8) i zatim koncentrovana pod sniženim pritiskom. Ostatak je razblažen dodatkom H2O (1200 ml) i ekstrahovan etil acetatom (1500 ml x 3). Organski slojevi su kombinovani, isprani zasićenim vodenim rastvorom soli (500 ml), osušeni i koncentrovani pod sniženim pritiskom radi dobijanja intermedijera 418 (85 g, prinos 96,3%) kao bele čvrste supstance. [0770] To a solution of adenosine (75 g, 281 mmol) in acetone (1200 ml) and DMF (400 ml) was added 2,2-dimethoxypropane (35.1 g, 336.8 mmol) and methanesulfonic acid (40.5 g, 421 mmol) under N2 atmosphere. The reaction mixture was stirred at 60°C for 6 h. The reaction mixture was treated with aqueous NaHCO3 (pH to 7-8) and then concentrated under reduced pressure. The residue was diluted with H 2 O (1200 ml) and extracted with ethyl acetate (1500 ml x 3). The organic layers were combined, washed with brine (500 mL), dried, and concentrated under reduced pressure to afford intermediate 418 (85 g, 96.3% yield) as a white solid.

Korak 2 Step 2

Priprema intermedijera 419 Preparation of intermediates 419

[0771] [0771]

[0772] U rastvor intermedijera 418 (87,8 g, 286 mmol) i imidazola (38,9 g, 571,4 mmol) u DMF-u (800 ml) dodat je TBDMSCl (51,67 g, 342,8 mmol) na sobnoj temperaturi u atmosferi N2. Reakcija je mešana na sobnoj temperaturi preko noći. Na sobnoj temperaturi je dodata voda (1000 ml), zatim je nastala bela čvrsta supstanca koja je uklonjena filtracijom. Čvrsta supstanca je sakupljena i rastvorena u etil acetatu (1500 ml) i isprana zasićenim vodenim rastvorom soli (500 ml). Organska faza je osušena iznad anhidrovanog Na2SO4, filtrirana i koncentrovana radi dobijanja intermedijera 419 (120 g, 99% prinos) kao bele čvrste supstance. [0772] To a solution of intermediate 418 (87.8 g, 286 mmol) and imidazole (38.9 g, 571.4 mmol) in DMF (800 mL) was added TBDMSCl (51.67 g, 342.8 mmol) at room temperature under N2 atmosphere. The reaction was stirred at room temperature overnight. Water (1000 ml) was added at room temperature, then a white solid formed which was removed by filtration. The solid was collected and dissolved in ethyl acetate (1500 mL) and washed with brine (500 mL). The organic phase was dried over anhydrous Na 2 SO 4 , filtered and concentrated to afford intermediate 419 (120 g, 99% yield) as a white solid.

Korak 3 Step 3

Priprema intermedijera 420 Preparation of intermediate 420

[0773] [0773]

[0774] Smeša intermedijera 419 (116,3 g, 275,9 mmol), DMAP (3,37 g, 27,6 mmol) i THF (1500 ml) mešana je na sobnoj temperaturi. Ukapavanjem je dodat Boc2O (150,5 g, 689,7 mmol). Smeša je mešana na sobnoj temperaturi tokom 2 sata. Smeša je uparena pod vakuumom. Ostatak je rastvoren u etil acetatu (1500 ml) i ispran zasićenim vodenim rastvorom soli (1000 ml). Organske faze su kombinovane, osušene iznad anhidrovanog Na2SO4, filtrirane i koncentrovane radi dobijanja intermedijera 420 (170 g, prinos 83%) kao bele čvrste supstance. [0774] A mixture of intermediate 419 (116.3 g, 275.9 mmol), DMAP (3.37 g, 27.6 mmol) and THF (1500 mL) was stirred at room temperature. Boc 2 O (150.5 g, 689.7 mmol) was added dropwise. The mixture was stirred at room temperature for 2 hours. The mixture was evaporated under vacuum. The residue was dissolved in ethyl acetate (1500 ml) and washed with saturated aqueous salt solution (1000 ml). The organic phases were combined, dried over anhydrous Na 2 SO 4 , filtered and concentrated to afford intermediate 420 (170 g, 83% yield) as a white solid.

Korak 4 Step 4

Priprema intermedijera 421 Preparation of intermediates 421

[0775] [0775]

[0776] U rastvor intermedijera 420 (176 g, 238,8 mmol) u THF-u (2000 ml) dodat je TBAF (1 M u THF-u, 238,8 ml, 238,8 mmol) ukapavanjem na sobnoj temperaturi u atmosferi N2. Reakciona smeša je mešana na sobnoj temperaturi tokom 1 sata. Smeša je sipana u vodu (2000 ml) i ekstrahovana etil acetatom (2000 ml x 3). Kombinovani organski slojevi su osušeni iznad Na2SO4, filtrirani i upareni radi dobijanja sirovog proizvoda. Ovaj ostatak je prečišćen fleš hromatografijom na koloni silika gela (eluent: petrol etar/etil acetat 10/1 do 1/1). Željene frakcije su sakupljene i rastvarač je uparen radi dobijanja intermedijera 421 (85 g, 72,5%) kao žutog ulja. [0776] To a solution of intermediate 420 (176 g, 238.8 mmol) in THF (2000 mL) was added TBAF (1 M in THF, 238.8 mL, 238.8 mmol) dropwise at room temperature under N2 atmosphere. The reaction mixture was stirred at room temperature for 1 hour. The mixture was poured into water (2000 ml) and extracted with ethyl acetate (2000 ml x 3). The combined organic layers were dried over Na 2 SO 4 , filtered and evaporated to give the crude product. This residue was purified by flash chromatography on a silica gel column (eluent: petroleum ether/ethyl acetate 10/1 to 1/1). The desired fractions were collected and the solvent was evaporated to give intermediate 421 (85 g, 72.5%) as a yellow oil.

Korak 5 Step 5

Priprema intermedijera 422 Preparation of intermediates 422

[0777] [0777]

[0778] U rastvor intermedijera 421 (1 g, 1,97 mmol), intermedijera 200 (509 mg, 1,97 mmol) i DIAD (1,19 g, 5,91 mmol) u THF-u (20 ml) dodat je PPh3(1,55 g, 5,91 mmol) na sobnoj temperaturi u atmosferi N2. Smeša je mešana na sobnoj temperaturi tokom 4 sata. Dodata je voda (40 ml) i smeša je ekstrahovana etil acetatom (3 x 50 ml). Organski slojevi su kombinovani, osušeni iznad Na2SO4, filtrirani i koncentrovani pod sniženim pritiskom radi dobijanja sirovog proizvoda. Ovaj ostatak je prečišćen fleš hromatografijom na koloni silika gela (eluent: petrolej/etil acetat od 10/1 do 2/1). Željene frakcije su sakupljene, i rastvarač je uparen radi dobijanja proizvoda kao žutog ulja. Ulje je prečišćeno pomoću HPLC na koloni: Phenomenex Gemini C18250 x 50 mm x10 µm; uslovi: A: voda (0,05% amonijum hidroksid V/V), B: MeCN; na početku: A (48%) i B (52%), na kraju: A (18%) i B (82%); vreme gradijenta (min) 30; 100% B vreme zadržavanja (min) 5; protok (ml/min) 90) radi dobijanja intermedijera 422 (650 mg, prinos 41%) kao bele čvrste supstance. [0778] To a solution of intermediate 421 (1 g, 1.97 mmol), intermediate 200 (509 mg, 1.97 mmol) and DIAD (1.19 g, 5.91 mmol) in THF (20 ml) was added PPh3 (1.55 g, 5.91 mmol) at room temperature under an atmosphere of N2. The mixture was stirred at room temperature for 4 hours. Water (40 mL) was added and the mixture was extracted with ethyl acetate (3 x 50 mL). The organic layers were combined, dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give the crude product. This residue was purified by flash chromatography on a silica gel column (eluent: petroleum/ethyl acetate from 10/1 to 2/1). The desired fractions were collected, and the solvent was evaporated to give the product as a yellow oil. The oil was purified by HPLC on a column: Phenomenex Gemini C18250 x 50 mm x 10 µm; conditions: A: water (0.05% ammonium hydroxide V/V), B: MeCN; at the beginning: A (48%) and B (52%), at the end: A (18%) and B (82%); gradient time (min) 30; 100% B retention time (min) 5; flow (ml/min) 90) to give intermediate 422 (650 mg, 41% yield) as a white solid.

Primer A93 Example A93

Priprema intermedijera 423 Preparation of intermediates 423

[0779] [0779]

[0780] U smešu intermedijera 421(2 g, 3,94 mmol), Et3N (0,797 g, 7,88 mmol) i DMAP(0,096 g, 0,788 mmol) mešanu u DCM-u (40 ml) na sobnoj temperaturi dodat je TosCl (1,127 g, 5,91 mmol). Reakciona smeša je mešana preko noći. Zatim je u smešu dodato 50 ml zasićenog NaHCO3i slojevi su razdvojeni. Vodeni sloj je ekstrahovan pomoću DCM (50 ml x 2). Kombinovani organski slojevi su osušeni iznad Na2SO4, filtrirani i koncentrovani pod vakuumom radi dobijanja sirovog proizvoda kao ulja. Sirovi proizvod je prečišćen na koloni (eluent: petrol etar/EtOAc odnos 10/1 do 3/1) radi dobijanja intermedijera 423 (1,25 g, prinos 45%) kao bele čvrste supstance. [0780] To a mixture of intermediate 421 (2 g, 3.94 mmol), Et3N (0.797 g, 7.88 mmol) and DMAP (0.096 g, 0.788 mmol) in DCM (40 mL) at room temperature was added TosCl (1.127 g, 5.91 mmol). The reaction mixture was stirred overnight. Then 50 ml of saturated NaHCO3 was added to the mixture and the layers were separated. The aqueous layer was extracted with DCM (50 ml x 2). The combined organic layers were dried over Na 2 SO 4 , filtered and concentrated in vacuo to give the crude product as an oil. The crude product was purified on a column (eluent: petroleum ether/EtOAc ratio 10/1 to 3/1) to give intermediate 423 (1.25 g, 45% yield) as a white solid.

Korak 2 Step 2

Priprema intermedijera 424 Preparation of intermediates 424

[0781] [0781]

[0782] U rastvor intermedijera 423 (1,1 g, 1,66 mmol), 3-brom-7-hidroksihinolina (0,372 g, 1,66 mmol) i DMF (40 ml) dodat je Cs2CO3(1,63 g, 4,98 mmol) na sobnoj temperaturi u atmosferi N2. Smeša je mešana na 40°C tokom 6 sati. Reakciona smeša je filtrirana i filtrat je uparen. Ostatak je prečišćen na koloni silika gela (eluent: petrol etar/etil acetat: odnos 20/1 do 0/1) radi dobijanja intermedijera 424 (1,1 g, prinos 87%) kao žutog ulja. [0782] To a solution of intermediate 423 (1.1 g, 1.66 mmol), 3-bromo-7-hydroxyquinoline (0.372 g, 1.66 mmol) and DMF (40 ml) was added Cs 2 CO 3 (1.63 g, 4.98 mmol) at room temperature under an atmosphere of N 2 . The mixture was stirred at 40°C for 6 hours. The reaction mixture was filtered and the filtrate was evaporated. The residue was purified on a silica gel column (eluent: petroleum ether/ethyl acetate: ratio 20/1 to 0/1) to give intermediate 424 (1.1 g, yield 87%) as a yellow oil.

Primer A94 Example A94

Korak 1 Step 1

Priprema intermedijera 425 Preparation of intermediates 425

[0783] [0783]

[0784] Smeša intermedijera 165 (300 mg, 0,393 mmol,) i rastvora NaOH (19,2 ml, 38,5 mmol, 2 M) u dioksanu (5 ml) refluktovana je na 60°C tokom 48 h. Smeša je ekstrahovana etil acetatom (10 ml x 3), organski slojevi su kombinovani i upareni pod vakuumom radi dobijanja intermedijera 425 (300 mg, prinos 42%) kao sirovog proizvoda. [0784] A mixture of intermediate 165 (300 mg, 0.393 mmol,) and a solution of NaOH (19.2 ml, 38.5 mmol, 2 M) in dioxane (5 ml) was refluxed at 60 °C for 48 h. The mixture was extracted with ethyl acetate (10 mL x 3), the organic layers were combined and evaporated in vacuo to afford intermediate 425 (300 mg, 42% yield) as crude product.

Korak 2 Step 2

Priprema intermedijera 426 Preparation of intermediates 426

[0785] [0785]

[0786] Rastvor intermedijera 425 (300 mg, 0,164 mmol) u trifluorsirćetnoj kiselini (5 ml) mešan je na 50°C tokom 1 h. Smeša je uparena pod vakuumom radi dobijanja intermedijera 426 (150 mg, prinos 75%) kao sirovog proizvoda. [0786] A solution of intermediate 425 (300 mg, 0.164 mmol) in trifluoroacetic acid (5 mL) was stirred at 50 °C for 1 h. The mixture was evaporated under vacuum to give intermediate 426 (150 mg, 75% yield) as crude product.

1 1

Primer A95 Example A95

Korak 1 Step 1

Priprema intermedijera 427 Preparation of intermediates 427

[0787] [0787]

[0788] U rastvor intermedijera 157 (4 g, 14,4 mmol) u THF-u (100 ml) dodat je LiHMDS (28,8 g, 1 M). Reakciona smeša je mešana na 0°C tokom 15 min, zatim je dodat BoC2O (6,3 g, 28,8 mmol). Reakciona smeša je mešana na sobnoj temperaturi još 30 min. Reakciona smeša je deaktivirana zasićenim vod. NH4Cl (50 ml) i ekstrahovana etil acetatom (50 ml x 2). Organski slojevi su kombinovani i upareni pod vakuumom radi dobijanja intermedijera 427 (5 g) kao sirovog proizvoda. [0788] To a solution of intermediate 157 (4 g, 14.4 mmol) in THF (100 ml) was added LiHMDS (28.8 g, 1 M). The reaction mixture was stirred at 0 °C for 15 min, then BoC 2 O (6.3 g, 28.8 mmol) was added. The reaction mixture was stirred at room temperature for another 30 min. The reaction mixture was quenched with saturated aq. NH 4 Cl (50 ml) and extracted with ethyl acetate (50 ml x 2). The organic layers were combined and evaporated under vacuum to give intermediate 427 (5 g) as crude product.

Korak 2 Step 2

Priprema intermedijera 428 Preparation of intermediates 428

[0789] [0789]

[0790] U rastvor intermedijera 427 (5,0 g, 13,25 mmol) u MeOH (25 ml) i DMF-u (25 ml) dodat je Pd(dppf)Cl2(0,970 g, 1,32 mmol) i Et3N (4,02 g, 39,76 mmol). Reakciona smeša je degasirana pod vakuumom i tri puta produvana gasovitim CO. Reakcija je mešana preko noći [0790] To a solution of intermediate 427 (5.0 g, 13.25 mmol) in MeOH (25 mL) and DMF (25 mL) was added Pd(dppf)Cl 2 (0.970 g, 1.32 mmol) and Et 3 N (4.02 g, 39.76 mmol). The reaction mixture was degassed under vacuum and purged with CO gas three times. The reaction was stirred overnight

2 2

u atmosferi CO na 120°C. Reakciona smeša je razblažena dodatkom H2O (100 ml) i zatim ekstrahovana etil acetatom (100 ml x 3). Organski sloj je ispran dodatkom H2O (100 ml) i osušen anhidrovanim Na2SO4i koncentrovan pod sniženim pritiskom. Sirovi proizvod je prečišćen hromatografijom na koloni silika gela (petrol etar/etil acetat: odnos 5/1 do petrol etar/etil acetat 2/1). Čiste frakcije su sakupljene i rastvarač je uparen pod vakuumom radi dobijanja intermedijera 428 (4,0 mg, prinos 85%). in a CO atmosphere at 120°C. The reaction mixture was diluted with H 2 O (100 mL) and then extracted with ethyl acetate (100 mL x 3). The organic layer was washed with H2O (100 mL) and dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate: ratio 5/1 to petroleum ether/ethyl acetate 2/1). Pure fractions were collected and the solvent was evaporated under vacuum to give intermediate 428 (4.0 mg, 85% yield).

Korak 3 Step 3

Priprema intermedijera 429 Preparation of intermediates 429

[0791] [0791]

[0792] U rastvor intermedijera 428 (4,0 g, 11,2 mmol) u THF-u (20 ml) dodat je LiAlH4(0,426 mg, 11,2 mmol). Reakciona smeša je mešana na sobnoj temperaturi tokom 3 h. Smeša je deaktivirana 10% vod. KOH (0,5 ml), filtrirana, i filtrat je koncentrovan pod sniženim pritiskom radi dobijanja intermedijera 429 (3,4 g, prinos 90%) kao ulja. [0792] To a solution of intermediate 428 (4.0 g, 11.2 mmol) in THF (20 mL) was added LiAlH 4 (0.426 mg, 11.2 mmol). The reaction mixture was stirred at room temperature for 3 h. The mixture is deactivated by 10% water. KOH (0.5 mL), filtered, and the filtrate was concentrated under reduced pressure to give intermediate 429 (3.4 g, 90% yield) as an oil.

Korak 4 Step 4

Priprema intermedijera 332 Preparation of intermediates 332

[0793] [0793]

[0794] U rastvor intermedijera 429 (1,3 g, 3,96 mmol) u DCM-u (20 ml) dodat je mezil hlorid (0,907 g, 7,92 mmol), DMAP (96,7 mg, 0,792 mmol) i Et3N (1,2 g, 11,88 mmol). Reakciona smeša je mešana preko noći na sobnoj temperaturi. [0794] To a solution of intermediate 429 (1.3 g, 3.96 mmol) in DCM (20 mL) was added mesyl chloride (0.907 g, 7.92 mmol), DMAP (96.7 mg, 0.792 mmol) and Et3N (1.2 g, 11.88 mmol). The reaction mixture was stirred overnight at room temperature.

[0795] Reakciona smeša je razblažena DCM-om (100 ml), i organska faza je zatim isprana vodenim rastvorom K2CO3(50 ml x 3). Organska faza je osušena iznad Na2SO4i zatim je koncentrovana pod sniženim pritiskom radi dobijanja intermedijera 332 kao žutog ulja koje je korišćeno u sledećem reakcionom koraku bez daljeg prečišćavanja. [0795] The reaction mixture was diluted with DCM (100 ml), and the organic phase was then washed with aqueous K 2 CO 3 (50 ml x 3). The organic phase was dried over Na 2 SO 4 and then concentrated under reduced pressure to give intermediate 332 as a yellow oil which was used in the next reaction step without further purification.

Primer A96 Example A96

Korak 1 Step 1

Priprema intermedijera 430 Preparation of intermediate 430

[0796] [0796]

[0797] Br2(0,89 ml) dodat je u rastvor 2-hidroksihinoksalina (1,5 g, 10,2 mmol) u HOAc (15 ml) i reakcija je mešana na sobnoj temperaturi tokom 6 sati. Čvrsta supstanca je filtrirana i isprana etil acetatom radi dobijanja intermedijera 430 (2,2 g, prinos: 95%) kao bele čvrste supstance. [0797] Br2 (0.89 mL) was added to a solution of 2-hydroxyquinoxaline (1.5 g, 10.2 mmol) in HOAc (15 mL) and the reaction was stirred at room temperature for 6 hours. The solid was filtered and washed with ethyl acetate to give intermediate 430 (2.2 g, yield: 95%) as a white solid.

Korak 2 Step 2

Priprema intermedijera 431 Preparation of intermediates 431

[0798] [0798]

4 4

[0799] POCl3(48,5 g, 316 mmol) dodat je u intermedijer 430 (2,2 g, 9,7 mmol). Smeša je mešana na 70°C tokom 2 sati. Smeša je polako sipana u vodu. Vod. NaHCO3je dodavan u smešu do prestanka razvijanja gasa. Smeša je ekstrahovana pomoću EtOAc. Organska faza je filtrirana i isprana zasićenim vodenim rastvorom soli. Organska faza je osušena iznad Na2SO4i koncentrovana radi dobijanja intermedijera 431 (2 g, prinos: 81%) [0799] POCl 3 (48.5 g, 316 mmol) was added to intermediate 430 (2.2 g, 9.7 mmol). The mixture was stirred at 70°C for 2 hours. The mixture was slowly poured into the water. Platoon. NaHCO3 was added to the mixture until gas evolution stopped. The mixture was extracted with EtOAc. The organic phase was filtered and washed with saturated aqueous salt solution. The organic phase was dried over Na2SO4 and concentrated to give intermediate 431 (2 g, yield: 81%)

Korak 3 Step 3

Priprema intermedijera 432 Preparation of intermediates 432

[0800] [0800]

[0801] Rastvor intermedijera 431 (100 mg, 0,41 mmol) u dioksanu (4 ml) i NH3.H2O(10 ml, 25%) mešan je u zaptivenoj epruveti na 110°C preko noći. Smeša je koncentrovana radi dobijanja sirovog intermedijera 432 (108 mg) kao žute čvrste supstance. [0801] A solution of intermediate 431 (100 mg, 0.41 mmol) in dioxane (4 ml) and NH 3 .H 2 O (10 ml, 25%) was stirred in a sealed tube at 110 °C overnight. The mixture was concentrated to afford crude intermediate 432 (108 mg) as a yellow solid.

ExampleA97 ExampleA97

Korak 1 Step 1

Priprema intermedijera 493 Preparation of intermediates 493

[0802] [0802]

[0803] Smeša intermedijera 408 (10 g, 54,88 mmol) u 0,5 M rastvoru 9-BBN u THF-u (439 ml, 219,5 mmol) mešana je na 50°C tokom 1 h u atmosferi N2. Smeša je ohlađena na sobnu temperaturu, zatim je dodat K3PO4(34,9 g, 164,6 mmol) u H2O (20 ml), pa onda THF (110 ml), intermedijer 181 (15,19 g, 54, 88 mmol) i Pd-118 (1788 mg, 2,74 mmol). Dobijena smeša je mešana na 50°C tokom 0,5 h. [0803] A mixture of intermediate 408 (10 g, 54.88 mmol) in a 0.5 M solution of 9-BBN in THF (439 ml, 219.5 mmol) was stirred at 50 °C for 1 h under N 2 . The mixture was cooled to room temperature, then K3PO4 (34.9 g, 164.6 mmol) in H2O (20 mL) was added, followed by THF (110 mL), intermediate 181 (15.19 g, 54.88 mmol), and Pd-118 (1788 mg, 2.74 mmol). The resulting mixture was stirred at 50°C for 0.5 h.

[0804] Smeša je koncentrovana. Ostatak je rastvoren u etil acetatu (400 ml), ispran vodom (400 ml) i zasićenim vodenim rastvorom soli (400 ml). Organska faza je osušena iznad Na2SO4, filtrirana i koncentrovana. Sirovi proizvod je prečišćen hromatografijom na koloni silika gela (petrol etar/etil acetat 10/1 do petrol etar/etil acetat 1/1). Čiste frakcije su sakupljene i rastvarač je uparen pod vakuumom radi dobijanja intermedijera 393 (19 mg, prinos 82%) kao čvrste supstance. [0804] The mixture is concentrated. The residue was dissolved in ethyl acetate (400 ml), washed with water (400 ml) and brine (400 ml). The organic phase was dried over Na2SO4, filtered and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate 10/1 to petroleum ether/ethyl acetate 1/1). Pure fractions were collected and the solvent was evaporated under vacuum to give intermediate 393 (19 mg, 82% yield) as a solid.

[0805] Sledeći intermedijeri su pripremljeni reakcionim protokolom koji je analogan protokolu korišćenom za pripremu intermedijera 393 koristeći odgovarajuće polazne supstance (Tabela 50). [0805] The following intermediates were prepared by a reaction protocol analogous to the protocol used for the preparation of intermediate 393 using the appropriate starting substances (Table 50).

Tabela 50: Table 50:

Korak 2 Step 2

Priprema intermedijera 494 Preparation of intermediates 494

[0806] [0806]

[0807] Intermedijer 493 (4 g, 10,46 mmol) i piridin (2,48 g, 31,39 mmol) rastvoreni su u DCM-u (50 ml) u atmosferi N2. Anhidrid trifluormetansulfonske kiseline (5,9 g, 20,93 mmol) dodat je na 0°C, i reakciona smeša je mešana tokom 0,5 sati. Reakciona smeša je zatim mešana na 25°C tokom 1 sata. Rastvarač je uklonjen pod vakuumom. Ostatak je prečišćen hromatografijom na koloni silika gela (odnos petrol etar/etil acetat 10/0 do odnosa petrol etar/etil acetat 4/1). Čiste frakcije su sakupljene, i rastvarač je uparen pod vakuumom radi dobijanja intermedijera 494 (3,5 mg, prinos 65%) kao bele čvrste supstance. [0807] Intermediate 493 (4 g, 10.46 mmol) and pyridine (2.48 g, 31.39 mmol) were dissolved in DCM (50 mL) under N 2 . Trifluoromethanesulfonic anhydride (5.9 g, 20.93 mmol) was added at 0 °C, and the reaction mixture was stirred for 0.5 h. The reaction mixture was then stirred at 25°C for 1 hour. The solvent was removed under vacuum. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate ratio 10/0 to petroleum ether/ethyl acetate ratio 4/1). Pure fractions were collected, and the solvent was evaporated under vacuum to afford intermediate 494 (3.5 mg, 65% yield) as a white solid.

[0808] Sledeći intermedijeri su pripremljeni reakcionim protokolom koji je analogan protokolu korišćenom za pripremu intermedijera 394 koristeći odgovarajuće polazne supstance (Tabela 51). [0808] The following intermediates were prepared by a reaction protocol analogous to the protocol used to prepare intermediate 394 using the appropriate starting substances (Table 51).

Tabela 51: Table 51:

Korak 3 Step 3

Priprema intermedijera 495 Preparation of intermediates 495

[0809] [0809]

[0810] 7H-pirolo[2,3-d]pirimidin, 2,4-dihlor-(1,24 g, 6,61 mmol) i Cs2CO3(3,23 g, 9,91 mmol) rastvoreni su u DMF-u (20 ml) u atmosferi N2. Zatim je dodat intermedijer 494. Reakciona smeša je mešana na 25°C tokom 12 sati. U smešu su dodati etil acetat (50 ml) i voda (50 ml). Organski sloj je razdvojen, ispran pomoću H2O i osušen (Na2SO4). Rastvarač je uklonjen pod sniženim pritiskom. Sirovi proizvod je prečišćen hromatografijom na koloni silika gela (petrol etar/etil acetat odnos 10/1 do petrol etar/etil acetat odnos 4/1). Čiste frakcije su sakupljene i rastvarač je uparen pod vakuumom radi dobijanja intermedijera 495 (900 mg, prinos 37%) kao žute čvrste supstance. [0810] 7H-pyrrolo[2,3-d]pyrimidine, 2,4-dichloro-(1.24 g, 6.61 mmol) and Cs 2 CO 3 (3.23 g, 9.91 mmol) were dissolved in DMF (20 mL) under N 2 . Intermediate 494 was then added. The reaction mixture was stirred at 25°C for 12 hours. Ethyl acetate (50 ml) and water (50 ml) were added to the mixture. The organic layer was separated, washed with H2O and dried (Na2SO4). The solvent was removed under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate ratio 10/1 to petroleum ether/ethyl acetate ratio 4/1). Pure fractions were collected and the solvent was evaporated under vacuum to give intermediate 495 (900 mg, 37% yield) as a yellow solid.

[0811] Sledeći intermedijeri su pripremljeni reakcionim protokolom koji je analogan protokolu korišćenom za pripremu intermedijera 495 koristeći odgovarajuće polazne supstance (Tabela 43). [0811] The following intermediates were prepared by a reaction protocol analogous to the protocol used for the preparation of intermediate 495 using the appropriate starting substances (Table 43).

Tabela 43: Table 43:

Primer A100 Example A100

[0812] [0812]

[0813] Rastvor intermedijera 533 (1,75 g, 3,1 mmol), 2,4-dimetoksibenzilamin hidrohlorida (2,6 g, 15,6 mmol) i DIPEA(1,2 g, 9,3 mmol) u n-BuOH (5 ml) mešan je na 140°C tokom 3 dana. Reakciona smeša je razblažena dodatkom CH2Cl2(30 ml) i isprana pomoću H2O (20 ml x 2). Organska faza je razdvojena i osušena sa Na2SO4i rastvarač je uklonjen pod vakuumom. Sirovi proizvod je prečišćen hromatografijom na koloni silika gela (petrol etar/etil acetat odnos 10/1 do petrol etar/etil acetat odnos 1/2) radi dobijanja intermedijera 534 (1,1 g, prinos 81%) kao žute čvrste supstance. [0813] A solution of intermediate 533 (1.75 g, 3.1 mmol), 2,4-dimethoxybenzylamine hydrochloride (2.6 g, 15.6 mmol) and DIPEA (1.2 g, 9.3 mmol) in n-BuOH (5 mL) was stirred at 140 °C for 3 days. The reaction mixture was diluted with CH 2 Cl 2 (30 mL) and washed with H 2 O (20 mL x 2). The organic phase was separated and dried with Na2SO4 and the solvent was removed under vacuum. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate ratio 10/1 to petroleum ether/ethyl acetate ratio 1/2) to afford intermediate 534 (1.1 g, 81% yield) as a yellow solid.

Primer A98 Example A98

Priprema intermedijera 526 Preparation of intermediates 526

[0814] [0814]

[0815] Intermedijer 525 (900 mg, 1,862 mmol), benzofenon imin (354,3 mg, 1,95 mmol), Pd(OAc)2(41,8 mg, 0,186 mmol), BINAP (115,9 mg, 0,186 mmol) i Cs2CO3(1213 mg, 3,72 mmol) rastvoreni su u toluenu (20 ml). Smeša je mešana na 110°C tokom 14 sati u atmosferi N2. Katalizator je filtriran i rastvarač je uparen. Ostatak je prečišćen fleš hromatografijom na koloni silika gela (elucioni gradijent: EtOAc/petrol etar od 1/15 do 1/1). Frakcije proizvoda su sakupljene i rastvarač je uparen radi dobijanja intermedijera 526 (660 mg, prinos 51%) kao žute čvrste supstance. [0815] Intermediate 525 (900 mg, 1.862 mmol), benzophenone imine (354.3 mg, 1.95 mmol), Pd(OAc)2 (41.8 mg, 0.186 mmol), BINAP (115.9 mg, 0.186 mmol) and Cs2CO3 (1213 mg, 3.72 mmol) were dissolved in toluene (20 mL). ml). The mixture was stirred at 110°C for 14 hours under N2 atmosphere. The catalyst was filtered and the solvent was evaporated. The residue was purified by flash chromatography on a silica gel column (elution gradient: EtOAc/petroleum ether from 1/15 to 1/1). The product fractions were collected and the solvent was evaporated to give intermediate 526 (660 mg, 51% yield) as a yellow solid.

1 1

B. Priprema jedinjenja i ilustrativni primeri B. Preparation of Compounds and Illustrative Examples

[0816] Jedinjenja koja ne spadaju u opseg zahteva 1 uključena su samo u svrhe reference. [0816] Compounds not falling within the scope of claim 1 are included for reference purposes only.

Primer B1 Example B1

Priprema jedinjenja 1 Preparation of compound 1

[0817] [0817]

[0818] Intermedijer 104 (300 mg, sirov, ≈ 0,568 mmol) rastvoren je u 5 ml 4 M HCl/MeOH. Smeša je mešana na sobnoj temperaturi tokom 3 sata. Rastvarač je koncentrovan pod vakuumom. Ostatak je rastvoren u 4 ml MeOH, i pH je podešen na oko pH = 9 pomoću zasićenog rastvora Na2CO3. Rastvarač je prečišćen putem preparativne HPLC (HPLC uslovi: kolona: Gemini 150*25 mm*5 µm; elucioni gradijent: 0,05% amonijak/CH3CN, od 81/19 do 71/29) radi dobijanja jedinjenja 1 (70 mg, prinos 30%) kao bele čvrste supstance. [0818] Intermediate 104 (300 mg, crude, ≈ 0.568 mmol) was dissolved in 5 ml of 4 M HCl/MeOH. The mixture was stirred at room temperature for 3 hours. The solvent was concentrated under vacuum. The residue was dissolved in 4 ml of MeOH, and the pH was adjusted to about pH = 9 with saturated Na 2 CO 3 solution. The solvent was purified by preparative HPLC (HPLC conditions: column: Gemini 150*25 mm*5 µm; elution gradient: 0.05% ammonia/CH3CN, from 81/19 to 71/29) to obtain compound 1 (70 mg, yield 30%) as a white solid.

Primer B2 Example B2

Priprema jedinjenja 2 Preparation of compound 2

[0819] [0819]

2 2

[0820] 4 M HCl u dioksanu (0,7 ml, 2,9 mmol) uz mešanje je dodat u rastvor intermedijera 105 (175,1 mg, sirov, ≈ 0,29 mmol) u MeOH (10 ml) na sobnoj temperaturi. Reakciona smeša je mešana na sobnoj temperaturi tokom 18 sata. Reakcija je deaktivirana dodatkom 1,5 ml 7 N rastvora NH3u MeOH. Rastvarači su upareni. Ostatak je rastvoren u DCM-u. Talog je uklonjen filtracijom. Filtrat je prečišćen na koloni SiO2, tip Grace Reveleris SRC, 12 g, Si 40, na Armen Spot II Ultimate sistemu za prečišćavanje koristeći DCM i MeOH kao eluent sa gradijentom koji polazi od 100% DCM i završava se sa 40% MeOH i 60% DCM. Frakcije koje sadrže proizvod su kombinovane i rastvarači su upareni, dajući 24,5 mg jedinjenja 2. [0820] 4 M HCl in dioxane (0.7 mL, 2.9 mmol) was added to a stirred solution of intermediate 105 (175.1 mg, crude, ≈ 0.29 mmol) in MeOH (10 mL) at room temperature. The reaction mixture was stirred at room temperature for 18 hours. The reaction was deactivated by the addition of 1.5 ml of a 7 N solution of NH3 in MeOH. Solvents are evaporated. The residue was dissolved in DCM. The precipitate was removed by filtration. The filtrate was purified on a SiO2 column, type Grace Reveleris SRC, 12 g, Si 40, on an Armen Spot II Ultimate purification system using DCM and MeOH as eluent with a gradient starting from 100% DCM and ending with 40% MeOH and 60% DCM. Fractions containing the product were combined and the solvents were evaporated, yielding 24.5 mg of compound 2.

Primer B3 Example B3

Priprema jedinjenja 2 Preparation of compound 2

[0821] [0821]

[0822] Intermedijer 89 (12,2 g, ≈15,751 mmol) rastvoren je u HCl/MeOH (220 ml, 4 M). Smeša je mešana na sobnoj temperaturi tokom 3 dana. Čvrsta supstanca je istaložena nakon 18 sati reakcije. Reakciona smeša je kombinovana sa još jednom šaržom reakcione smeše (1 g intermedijera 89). Dobijena čvrsta supstanca je filtrirana kroz levak i sakupljena. Ostatak je trituriran vodom, i pH je podešen na oko 8 postepenim dodavanjem čvrstog K2CO3. Dobijena čvrsta supstanca je filtrirana kroz Bihnerov levak, isprana vodom (100 ml*5) i sakupljena, zatim liofilizovana radi dobijanja jedinjenja 2 (5,95 g, prinos 73%) kao bele čvrste supstance. [0822] Intermediate 89 (12.2 g, ≈15.751 mmol) was dissolved in HCl/MeOH (220 mL, 4 M). The mixture was stirred at room temperature for 3 days. The solid substance was precipitated after 18 hours of reaction. The reaction mixture was combined with another batch of reaction mixture (1 g of intermediate 89). The resulting solid was filtered through a funnel and collected. The residue was triturated with water, and the pH was adjusted to about 8 by stepwise addition of solid K 2 CO 3 . The resulting solid was filtered through a Bichner funnel, washed with water (100 ml*5) and collected, then lyophilized to give compound 2 (5.95 g, 73% yield) as a white solid.

Primer B4 Example B4

Priprema jedinjenja 3 Preparation of compound 3

[0823] [0823]

[0824] U rastvor intermedijera 74 (249 mg, 0,405 mmol) u DCM-u (3,5 ml) dodata je TFA (0,8 ml, 10,5 mmol) i smeša je mešana na rt tokom 5 dana. Smeša je uparena pod vakuumom. Ostatak je rastvoren u MeOH (6 ml) i dodata je HCl (3 M u CPME) (1,5 ml, 4,5 mmol), i smeša je mešana preko noći na sobnoj temperaturi. Smeša je deaktivirana pomoću NH3u MeOH (7 N) i uparena pod vakuumom. Ostatak je prenet u DCM/MeOH (1/1), uklonjen filtracijom, i filtrat je uparen pod vakuumom. Ostaci su prečišćeni pomoću preparativne LC (nepravilni SiOH, 15-40 µm, 10 g, Merck, suvo nanošenje (Celite®), elucioni gradijent mobilne faze: od DCM:MeOH/vod. NH3(9:1) od 97,5:2,5 do 87,5: 12,5) radi dobijanja jedinjenja 3 kao bele čvrste supstance (156 mg, prinos 73%). [0824] To a solution of intermediate 74 (249 mg, 0.405 mmol) in DCM (3.5 mL) was added TFA (0.8 mL, 10.5 mmol) and the mixture was stirred at rt for 5 days. The mixture was evaporated under vacuum. The residue was dissolved in MeOH (6 mL) and HCl (3 M in CPME) (1.5 mL, 4.5 mmol) was added, and the mixture was stirred overnight at room temperature. The mixture was quenched with NH 3 in MeOH (7 N) and evaporated under vacuum. The residue was taken up in DCM/MeOH (1/1), removed by filtration, and the filtrate was evaporated under vacuum. The residue was purified by preparative LC (irregular SiOH, 15-40 µm, 10 g, Merck, dry application (Celite®), mobile phase elution gradient: from DCM:MeOH/aq NH3(9:1) from 97.5:2.5 to 87.5:12.5) to give compound 3 as a white solid (156 mg, 73% yield).

Primer B5 Example B5

Priprema jedinjenja 4 Preparation of compound 4

[0825] [0825]

4 4

[0826] U rastvor intermedijera 86 (750 mg, ≈0,71 mmol) u MeOH (40 ml) dodata je 4 M HCl u MeOH (20 ml) na rt. Smeša je nakon toga mešana na 50°C tokom 12 sati. Rastvarač je koncentrovan pod vakuumom. Ostaci su rastvoreni u 10 ml MeOH, i pH je podešen na oko 8 sa NaHCO3. Smeša je filtrirana, i rastvarač je prečišćen putem preparativne HPLC (elucioni gradijent: 0,05% NH3.H2O u MeOH/0,05% NH3.H2O u H2O). Željene frakcije su kombinovane, i rastvarač je uparen radi dobijanja jedinjenja 4 kao bele čvrste supstance (207 mg, 61%). [0826] To a solution of intermediate 86 (750 mg, ≈0.71 mmol) in MeOH (40 mL) was added 4 M HCl in MeOH (20 mL) at rt. The mixture was then stirred at 50°C for 12 hours. The solvent was concentrated under vacuum. The residue was dissolved in 10 ml of MeOH, and the pH was adjusted to about 8 with NaHCO 3 . The mixture was filtered, and the solvent was purified by preparative HPLC (elution gradient: 0.05% NH3.H2O in MeOH/0.05% NH3.H2O in H2O). The desired fractions were combined, and the solvent was evaporated to give compound 4 as a white solid (207 mg, 61%).

[0827] Sledeća jedinjenja su pripremljena analognim protokolom reakcije kao primer B1, B2, B3, B4, B5 ili B20 (dalje u eksperimentalnom delu) koristeći odgovarajuće polazne supstance (Tabela 21). Jedinjenja 55, 57, 57a i 61 su dobijena u E konfiguraciji. [0827] The following compounds were prepared by an analogous reaction protocol as example B1, B2, B3, B4, B5 or B20 (further in the experimental section) using the appropriate starting substances (Table 21). Compounds 55, 57, 57a and 61 were obtained in the E configuration.

Tabela 21: Table 21:

Jedinjenje Struktura Reakcioni Polazne Compound Structure Reactions Starting

Jedinjenje Struktura Reakcioni Polazne Compound Structure Reactions Starting

Jedinjenje Struktura Reakcioni Polazne Compound Structure Reactions Starting

Jedinjenje Struktura Reakcioni Polazne Compound Structure Reactions Starting

Jedinjenje Struktura Reakcioni Polazne Compound Structure Reactions Starting

Jedinjenje Struktura Reakcioni Polazne Compound Structure Reactions Starting

1 1

Jedinjenje Struktura Reakcioni Polazne Compound Structure Reactions Starting

2 2

Jedinjenje Struktura Reakcioni Polazne Compound Structure Reactions Starting

Jedinjenje Struktura Reakcioni Polazne Compound Structure Reactions Starting

4 4

Jedinjenje Struktura Reakcioni Polazne Compound Structure Reactions Starting

Jedinjenje Struktura Reakcioni Polazne Compound Structure Reactions Starting

Jedinjenje Struktura Reakcioni Polazne Compound Structure Reactions Starting

Jedinjenje Struktura Reakcioni Polazne Compound Structure Reactions Starting

Jedinjenje Struktura Reakcioni Polazne Compound Structure Reactions Starting

Jedinjenje Struktura Reakcioni Polazne Compound Structure Reactions Starting

Jedinjenje Struktura Reakcioni Polazne Compound Structure Reactions Starting

1 1

Jedinjenje Struktura Reakcioni Polazne Compound Structure Reactions Starting

2 2

Jedinjenje Struktura Reakcioni Polazne Compound Structure Reactions Starting

Jedinjenje Struktura Reakcioni Polazne Compound Structure Reactions Starting

4 4

Jedinjenje Struktura Reakcioni Polazne Compound Structure Reactions Starting

Jedinjenje Struktura Reakcioni Polazne Compound Structure Reactions Starting

Jedinjenje Struktura Reakcioni Polazne Compound Structure Reactions Starting

Jedinjenje Struktura Reakcioni Polazne Compound Structure Reactions Starting

Jedinjenje Struktura Reakcioni Polazne Compound Structure Reactions Starting

Jedinjenje Struktura Reakcioni Polazne Compound Structure Reactions Starting

4 4

Jedinjenje Struktura Reakcioni Polazne Compound Structure Reactions Starting

41 41

Jedinjenje Struktura Reakcioni Polazne Compound Structure Reactions Starting

42 42

Jedinjenje Struktura Reakcioni Polazne Compound Structure Reactions Starting

4 4

Jedinjenje Struktura Reakcioni Polazne Compound Structure Reactions Starting

44 44

Jedinjenje Struktura Reakcioni Polazne Compound Structure Reactions Starting

4 4

Primer B6 Example B6

Priprema jedinjenja 67 i jedinjenja 68 Preparation of Compound 67 and Compound 68

[0828] [0828]

4 4

[0829] Intermedijer 140 (210 mg, sirov, ≈0,399 mmol) rastvoren je u 5 ml HCl/MeOH. Smeša je mešana na sobnoj temperaturi tokom 7 sati. Reakcija je deaktivirana dodatkom NH3/MeOH radi podešavanja pH na oko 8 na 0°C. Dobijena čvrsta supstanca je zatim uklonjena filtracijom i isprana pomoću CH2Cl2(10 ml), i kombinovani organski filtrat je koncentrovan pod sniženim pritiskom radi dobijanja sirovog proizvoda. Ostatak je prečišćen putem preparativne HPLC (HPLC uslovi: kolone: Phenomenex Gemini 150*25 mm*10 um; elucioni gradijent mobilne faze sa 21% vode u ACN;) radi dobijanja jedinjenja 67 (40 mg) i jedinjenja 68 (52 mg) kao bele čvrste supstance. [0829] Intermediate 140 (210 mg, crude, ≈0.399 mmol) was dissolved in 5 mL of HCl/MeOH. The mixture was stirred at room temperature for 7 hours. The reaction was quenched by addition of NH3/MeOH to adjust the pH to about 8 at 0°C. The resulting solid was then removed by filtration and washed with CH 2 Cl 2 (10 mL), and the combined organic filtrate was concentrated under reduced pressure to afford the crude product. The residue was purified by preparative HPLC (HPLC conditions: column: Phenomenex Gemini 150*25 mm*10 µm; mobile phase gradient elution with 21% water in ACN;) to give compound 67 (40 mg) and compound 68 (52 mg) as white solids.

Primer B7 Example B7

[0830] [0830]

[0831] Reakciona smeša intermedijera 85 (150 mg, ≈0,233 mmol) u 5 ml smeše rastvarača AcOH, vode i THF u odnosu 13:7:3) mešana je preko noći na 60°C. Smeša je zatim mešana na 80°C tokom 1 dana. Rastvarač je koncentrovan pod vakuumom. Ostatak je rastvoren u 4 ml [0831] A reaction mixture of intermediate 85 (150 mg, ≈0.233 mmol) in 5 ml of a solvent mixture of AcOH, water and THF in the ratio 13:7:3) was stirred overnight at 60°C. The mixture was then stirred at 80°C for 1 day. The solvent was concentrated under vacuum. The residue was dissolved in 4 ml

4 4

MeOH, i pH je podešen na oko 9 pomoću čvrstog Na2CO3. Rastvarač je prečišćen putem preparativne HPLC (HPLC uslovi: kolone: Gemini 150*25 mm*5 µM; elucioni gradijent sa vodom (0,05% amonijum hidroksid V/V):ACN od 97:3 do 67:33) radi dobijanja jedinjenja 69 kao bele čvrste supstance. (13 mg, prinos 14%). MeOH, and the pH was adjusted to about 9 with solid Na2CO3. The solvent was purified by preparative HPLC (HPLC conditions: columns: Gemini 150*25 mm*5 µM; gradient elution with water (0.05% ammonium hydroxide V/V):ACN from 97:3 to 67:33) to give compound 69 as a white solid. (13 mg, yield 14%).

Primer B8 Example B8

[0832] [0832]

[0833] Intermedijer 152 (425 mg, 0,927 mmol) rastvoren je u mešanom rastvoru AcOH (22 ml), THF (5 ml) i H2O (12 ml). Smeša je mešana na 50°C tokom 12 sati. Rastvarač je koncentrovan pod vakuumom. Sirovi proizvod je prečišćen pomoću preparativne HPLC (elucioni gradijent: 0,05% NH3.H2O u MeOH/0,05% NH3.H2O u H2O). Kombinovani rastvarač je uparen radi dobijanja željenog jedinjenja 70 kao čvrste supstance (69,3 mg, prinos 18%). [0833] Intermediate 152 (425 mg, 0.927 mmol) was dissolved in a mixed solution of AcOH (22 ml), THF (5 ml) and H 2 O (12 ml). The mixture was stirred at 50°C for 12 hours. The solvent was concentrated under vacuum. The crude product was purified by preparative HPLC (elution gradient: 0.05% NH3.H2O in MeOH/0.05% NH3.H2O in H2O). The combined solvent was evaporated to give the desired compound 70 as a solid (69.3 mg, 18% yield).

Primer B9 Example B9

[0834] [0834]

[0835] U rastvor intermedijera 59 (187 mg, ≈0,18 mmol) u 1,4-dioksanu (5 ml) dodata je 4 M HCl u dioksanu (0,46 ml, 1,8 mmol). Reakciona smeša je mešana na sobnoj temperaturi tokom 18 sata. Reakcija je deaktivirana dodatkom 1,5 ml 7 N rastvora NH3u MeOH. Rastvarači [0835] To a solution of intermediate 59 (187 mg, ≈0.18 mmol) in 1,4-dioxane (5 mL) was added 4 M HCl in dioxane (0.46 mL, 1.8 mmol). The reaction mixture was stirred at room temperature for 18 hours. The reaction was deactivated by the addition of 1.5 ml of a 7 N solution of NH3 in MeOH. Solvents

4 4

su upareni. Ostatak je rastvoren u dihlormetanu sa metanolom ( u dovoljnoj količini) i zatim prečišćen na koloni SiO2, tip Grace Reveleris SRC, 12 g, Si 40, na Armen Spot II Ultimate sistemu za prečišćavanje koristeći dihlormetan i metanol kao eluent sa gradijentom polazeći od 100% DCM za 5 zapremina kolone i završavajući se na 40% MeOH i 60% DCM-a za 25 zapremina kolone. Frakcije koje sadrže proizvod su kombinovane i rastvarači su upareni, dajući 62 mg sirove smeše proizvoda. Sirova smeša proizvoda je prečišćena pomoću prep. HPLC (stacionarna faza: RP XBridge Prep C18 OBD-10 µm, 30x150 mm, mobilna faza: 0,25% NH4HCO3rastvor u vodi, CH3CN), dajući jedinjenje 71 (5,5 mg, prinos 6%). are paired. The residue was dissolved in dichloromethane with methanol (in sufficient amount) and then purified on a SiO2 column, Grace Reveleris SRC type, 12 g, Si 40, on an Armen Spot II Ultimate purification system using dichloromethane and methanol as eluent with a gradient starting from 100% DCM for 5 column volumes and ending with 40% MeOH and 60% DCM for 25 column volumes. Fractions containing the product were combined and the solvents were evaporated, yielding 62 mg of crude product mixture. The crude product mixture was purified using prep. HPLC (stationary phase: RP XBridge Prep C18 OBD-10 µm, 30x150 mm, mobile phase: 0.25% NH4HCO3 aqueous solution, CH3CN), affording compound 71 (5.5 mg, 6% yield).

Primer B10 Example B10

Priprema jedinjenja 1a Preparation of compound 1a

[0836] [0836]

[0837] U rastvor intermedijera 100 (9,26 mg, ≈17,5 mmol) u 1,4-dioksanu (300 ml) dodata je 4 M HCl u 1,4-dioksanu (43,8 ml, 175 mmol). Reakciona smeša je mešana na sobnoj temperaturi tokom 4 sata. Reakciona smeša je sipana u laboratorijsku čašu sa DIPE (1 l). Suspenzija je mešana tokom 20 minuta, i rastvarači su zatim uklonjeni dekantovanjem. Preostali talog je prekristalisan iz EtOH. Talog je uklonjen filtracijom, ispran pomoću DIPE i zatim osušen pod vakuumom na 50°C, dajući jedinjenje 1a kao so sa 2 ekvivalenta HCl (8,33 g, kvantitativni prinos). [0837] To a solution of intermediate 100 (9.26 mg, ≈17.5 mmol) in 1,4-dioxane (300 mL) was added 4 M HCl in 1,4-dioxane (43.8 mL, 175 mmol). The reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was poured into a laboratory beaker with DIPE (1 L). The suspension was stirred for 20 minutes, and the solvents were then removed by decantation. The remaining precipitate was recrystallized from EtOH. The precipitate was removed by filtration, washed with DIPE and then dried under vacuum at 50 °C to give compound 1a as a salt with 2 equivalents of HCl (8.33 g, quantitative yield).

Primer B11 Example B11

Priprema jedinjenja 72 (putem intermedijera 156) Preparation of compound 72 (via intermediate 156)

4 4

Korak a: Step a:

[0838] [0838]

[0839] Anhidrid izobuterne kiseline (2,36 ml, 14,2 mmol) uz mešanje je dodat u rastvor jedinjenja 22 (688,3 mg, 1,418 mmol) u piridinu (25 ml, 310,361 mmol) na rt. Nakon dodavanja, reakciona smeša je mešana na 50°C tokom 18 sati. Rastvarači su upareni. Ostatak je zajedno uparen sa toluenom. Ostatak je rastvoren u DCM-u i prečišćen na koloni SiO2, tip Grace Reveleris SRC, 40 g, Si 40, na Armen Spot II Ultimate sistemu za prečišćavanje koristeći DCM i MeOH kao eluent sa gradijentom polazeći od 100% DCM za 5 zapremina kolone i završavajući se na 40% MeOH i 60% DCM za 30 zapremina kolone. Željene frakcije su kombinovane i rastvarači su upareni, dajući 0,94 g intermedijera 156. [0839] Isobutyric anhydride (2.36 mL, 14.2 mmol) was added to a solution of compound 22 (688.3 mg, 1.418 mmol) in pyridine (25 mL, 310.361 mmol) at rt with stirring. After the addition, the reaction mixture was stirred at 50°C for 18 hours. Solvents are evaporated. The residue was co-evaporated with toluene. The residue was dissolved in DCM and purified on a SiO2 column, Grace Reveleris SRC type, 40 g, Si 40, on an Armen Spot II Ultimate purification system using DCM and MeOH as eluent with a gradient starting from 100% DCM for 5 column volumes and ending with 40% MeOH and 60% DCM for 30 column volumes. The desired fractions were combined and the solvents were evaporated, yielding 0.94 g of intermediate 156.

Korak b: Step b:

[0840] [0840]

[0841] Rastvor intermedijera 156 (0,94 g, 1,372 mmol) i SOCl2(99,493 µl, 1,372 mmol) u MeOH (20 ml, 0,791 g/ml, 493,725 mmol) mešan je i zagrevan na 110°C koristeći mikrotalasno zračenje tokom 5 sati. Rastvarači su upareni. Ostatak je rastvoren u DCM-u i [0841] A solution of intermediate 156 (0.94 g, 1.372 mmol) and SOCl 2 (99.493 µl, 1.372 mmol) in MeOH (20 ml, 0.791 g/ml, 493.725 mmol) was stirred and heated at 110°C using microwave irradiation for 5 h. Solvents are evaporated. The residue was dissolved in DCM and

41 41

prečišćen na koloni SiO2, tip Grace Reveleris SRC, 12 g, Si 40, na Armen Spot II Ultimate sistemu za prečišćavanje koristeći DCM i MeOH kao eluent sa gradijentom polazeći od 100% DCM za 10 zapremina kolona i završavajući se na 20% MeOH i 80% DCM za 30 zapremina kolone. Frakcije koje sadrže proizvod su kombinovane i rastvarači su upareni, dajući jedinjenje 72 (.HCl) (0,66 g, prinos 74%). purified on a SiO2 column, Grace Reveleris SRC type, 12 g, Si 40, on an Armen Spot II Ultimate purification system using DCM and MeOH as eluent with a gradient starting from 100% DCM for 10 column volumes and ending with 20% MeOH and 80% DCM for 30 column volumes. Fractions containing the product were combined and the solvents were evaporated to give compound 72 (.HCl) (0.66 g, 74% yield).

[0842] Sledeća jedinjenja su pripremljena analognim reakcionim protokolom iz primera B11 koristeći odgovarajuće polazne supstance (Tabela 22). [0842] The following compounds were prepared by an analogous reaction protocol from Example B11 using the appropriate starting substances (Table 22).

Tabela 22: Table 22:

Primer B12 Example B12

Priprema jedinjenja 74 Preparation of compound 74

[0843] [0843]

[0844] U rastvor intermedijera 160 (3,45 g, 6,9 mmol) u MeOH (10 ml) dodat je HCl/MeOH (4 N, 10 ml), i smeša je mešana na sobnoj temperaturi tokom 1 sata. [0844] To a solution of intermediate 160 (3.45 g, 6.9 mmol) in MeOH (10 mL) was added HCl/MeOH (4 N, 10 mL), and the mixture was stirred at room temperature for 1 hour.

[0845] Smeša je liofilizovana radi dobijanja frakcije 1 sirovog jedinjenja 74 koje je prečišćeno pomoću prep-HPLC (kolona: Phenomenex Synergi Max-RP 250*80 mm 10 µm, uslovi: voda (0,05% amonijum hidroksid V/V)-ACN, početak B: 30%, kraj B: 60, vreme trajanja gradijenta (min): 22, protok (ml/min): 120). Željene frakcije su sakupljene i liofilizovane radi dobijanja frakcije 2 sirovog jedinjenja 74 koja je dalje prečišćena pomoću prep-HPLC (kolona Phenomenex Gemini 150*25 mm*10 µm, uslov: gradijent voda (0,05% amonijum hidroksid V/V)-ACN. Željene frakcije su sakupljene i liofilizovane radi dobijanja jedinjenja 74 (1383 mg, prinos: 43,1%) kao čvrste supstance. [0845] The mixture was lyophilized to obtain fraction 1 of crude compound 74 which was purified by prep-HPLC (column: Phenomenex Synergi Max-RP 250*80 mm 10 µm, conditions: water (0.05% ammonium hydroxide V/V)-ACN, start B: 30%, end B: 60, gradient time (min): 22, flow (ml/min): 120). The desired fractions were collected and lyophilized to obtain fraction 2 of crude compound 74 which was further purified by prep-HPLC (Column Phenomenex Gemini 150*25 mm*10 µm, condition: water (0.05% ammonium hydroxide V/V)-ACN gradient). The desired fractions were collected and lyophilized to obtain compound 74 (1383 mg, yield: 43.1%) as a solid.

[0846] Oblici soli jedinjenja 74 pripremljeni su u skladu sa postupcima iz struke koji su poznati stručnjaku (Tabela 44). [0846] Salt forms of compound 74 were prepared according to procedures known to those skilled in the art (Table 44).

Tabela 44: Table 44:

Primer B13 Priprema jedinjenja 75 Example B13 Preparation of compound 75

[0847] [0847]

41 41

[0848] Rastvor intermedijera 163 (680 mg, ≈1,04 mmol) u MeOH ( u dovoljnoj količini) rastvoren je u HCl/MeOH (4 M, 15 ml), mešan na sobnoj temperaturi tokom 2 sata. Smeša je zalužena pomoću NH3.H2O do pH > 7. Rastvor je ispran pomoću H2O (100 ml), ekstrahovan etil acetatom (150 ml x 3). Kombinovani organski slojevi su osušeni (Na2SO4), filtrirani i koncentrovani pod vakuumom radi dobijanja sirovog proizvoda kao smeđe čvrste supstance. Sirovi proizvod je prečišćen pomoću prep-HPLC (kolona: Waters Xbridge Prep OBD C18 150x30 mm, 5 µm; uslovi: gradijent voda (0,05% amonijum hidroksid V/V)-MeOH). Željene frakcije su sakupljene i liofilizovane radi dobijanja jedinjenja 75 (129,8 mg, prinos: 26,4%) kao bele čvrste supstance. [0848] A solution of intermediate 163 (680 mg, ≈1.04 mmol) in MeOH (in sufficient amount) was dissolved in HCl/MeOH (4 M, 15 mL), stirred at room temperature for 2 hours. The mixture was basified with NH 3 .H 2 O to pH > 7. The solution was washed with H 2 O (100 ml), extracted with ethyl acetate (150 ml x 3). The combined organic layers were dried (Na 2 SO 4 ), filtered and concentrated in vacuo to give the crude product as a brown solid. The crude product was purified by prep-HPLC (column: Waters Xbridge Prep OBD C18 150x30 mm, 5 µm; conditions: gradient water (0.05% ammonium hydroxide V/V)-MeOH). The desired fractions were collected and lyophilized to give compound 75 (129.8 mg, yield: 26.4%) as a white solid.

Primer B14 Example B14

Priprema jedinjenja 76 Preparation of compound 76

[0849] [0849]

[0850] Smeša intermedijera 167 (250 mg) i K2CO3(185,3 mg, 1,34 mmol) u MeOH (3 ml) mešana je na 60°C tokom 1 h. Smeša je filtrirana i uparena pod vakuumom radi dobijanja sirovog proizvoda. On je prečišćen pomoću preparativne HPLC (kolona: Waters Xbridge Prep OBD C18150x30 mm, 5 µm, uslovi: gradijent voda (0,05% amonijum hidroksid V/V)-MeOH). Željene frakcije su sakupljene i rastvarač je uparen radi dobijanja jedinjenja 76 kao bele čvrste supstance (82,2 mg, prinos 45,3%). [0850] A mixture of intermediate 167 (250 mg) and K 2 CO 3 (185.3 mg, 1.34 mmol) in MeOH (3 mL) was stirred at 60 °C for 1 h. The mixture was filtered and evaporated under vacuum to give the crude product. It was purified by preparative HPLC (column: Waters Xbridge Prep OBD C18150x30 mm, 5 µm, conditions: gradient water (0.05% ammonium hydroxide V/V)-MeOH). The desired fractions were collected and the solvent was evaporated to give compound 76 as a white solid (82.2 mg, 45.3% yield).

Primer B15 Example B15

Priprema jedinjenja 77 Preparation of compound 77

[0851] [0851]

[0852] Smeša intermedijera 169 (120 mg, ≈0,185 mmol) i K2CO3(76,40 mg, 0,554 mmol) u metanolu (3 ml) mešana je na 60°C tokom 1 h. Smeša je filtrirana i uparena pod vakuumom radi dobijanja sirovog proizvoda. Sirovi proizvod je prečišćen pomoću prep-HPLC (kolona: Waters Xbridge Prep OBD C18150x30 mm, 5 µm, uslovi: gradijent voda (0,05% amonijum hidroksid V/V)-MeOH). Željene frakcije su sakupljene i rastvarač je uparen radi dobijanja jedinjenja 77 kao bele čvrste supstance (21,4 mg, prinos 29,4%). [0852] A mixture of intermediate 169 (120 mg, ≈0.185 mmol) and K 2 CO 3 (76.40 mg, 0.554 mmol) in methanol (3 ml) was stirred at 60 °C for 1 h. The mixture was filtered and evaporated under vacuum to give the crude product. The crude product was purified by prep-HPLC (column: Waters Xbridge Prep OBD C18150x30 mm, 5 µm, conditions: gradient water (0.05% ammonium hydroxide V/V)-MeOH). The desired fractions were collected and the solvent was evaporated to give compound 77 as a white solid (21.4 mg, 29.4% yield).

[0853] Sledeća jedinjenja su pripremljena reakcionim protokolom koji je analogan protokolu korišćenom za pripremu jedinjenja 77 koristeći odgovarajuće polazne supstance (Tabela 48). [0853] The following compounds were prepared by a reaction protocol analogous to the protocol used for the preparation of compound 77 using the appropriate starting materials (Table 48).

Tabela 48: Table 48:

Primer B16 Example B16

41 41

Priprema jedinjenja 78 Preparation of compound 78

[0854] [0854]

[0855] Smeša intermedijera 171 (160 mg, ≈0,273 mmol) i K2CO3(113,073 mg, 0,819 mmol) u metanolu (3 ml) mešana je na 50°C tokom 1 h. Smeša je filtrirana i uparena pod vakuumom radi dobijanja sirovog proizvoda. On je prečišćen pomoću prep-HPLC (kolona: Waters Xbridge Prep OBD C18150x30 mm, 5 µm, uslovi: gradijent voda (0,05% amonijum hidroksid V/V)-MeOH). Željene frakcije su sakupljene i rastvarač je uparen radi dobijanja Jedinjenja 78 (87,2 mg, prinos 75,3%) kao bele čvrste supstance. [0855] A mixture of intermediate 171 (160 mg, ≈0.273 mmol) and K 2 CO 3 (113.073 mg, 0.819 mmol) in methanol (3 ml) was stirred at 50 °C for 1 h. The mixture was filtered and evaporated under vacuum to give the crude product. It was purified by prep-HPLC (column: Waters Xbridge Prep OBD C18150x30 mm, 5 µm, conditions: gradient water (0.05% ammonium hydroxide V/V)-MeOH). The desired fractions were collected and the solvent was evaporated to give Compound 78 (87.2 mg, 75.3% yield) as a white solid.

Primer B17 Example B17

Priprema jedinjenja 79 Preparation of compound 79

[0856] [0856]

[0857] Smeša intermedijera 173 (250 mg, ≈0,241 mmol) i K2CO3(99,6 mg, 0,72 mmol) u metanolu (3 ml) mešana je na 50°C tokom 1 h. Smeša je filtrirana i uparena pod vakuumom radi dobijanja sirovog proizvoda. On je prečišćen pomoću preparativne HPLC (kolona: Waters Xbridge Prep OBD C18150x30 mm, 5 µm, uslovi: gradijent voda (0,05% amonijum hidroksid V/V)-MeOH). Željene frakcije su sakupljene i rastvarač je uparen radi dobijanja Jedinjenja 79 (96,1 mg, prinos 94,5%) kao bele čvrste supstance. [0857] A mixture of intermediate 173 (250 mg, ≈0.241 mmol) and K 2 CO 3 (99.6 mg, 0.72 mmol) in methanol (3 ml) was stirred at 50 °C for 1 h. The mixture was filtered and evaporated under vacuum to give the crude product. It was purified by preparative HPLC (column: Waters Xbridge Prep OBD C18150x30 mm, 5 µm, conditions: gradient water (0.05% ammonium hydroxide V/V)-MeOH). The desired fractions were collected and the solvent was evaporated to give Compound 79 (96.1 mg, 94.5% yield) as a white solid.

41 41

[0858] Sledeće jedinjenje je pripremljeno analognim reakcionim protokolom za jedinjenje 79 koristeći odgovarajuće polazne supstance (Tabela 45). [0858] The following compound was prepared by an analogous reaction protocol to compound 79 using the appropriate starting materials (Table 45).

Tabela 45: Table 45:

Primer B18 Example B18

Priprema jedinjenja 80 Preparation of compound 80

[0859] [0859]

[0860] Smeša intermedijera 179 (350 mg) i K2CO3(102 mg, 0,74 mmol) u metanolu (3 ml) mešana je na 60°C tokom 1 h. Smeša je filtrirana i uparena pod vakuumom radi dobijanja sirovog proizvoda. Sirovi proizvod je prečišćen pomoću prep-HPLC (kolona: Waters Xbridge Prep OBD C18 150x30 mm, 5 µm, uslovi: gradijent voda (0,05% amonijum hidroksid V/V)-ACN). Željene frakcije su sakupljene i rastvarač je uparen radi dobijanja Jedinjenja 80 (113,3 mg, prinos 94,9%) kao bele čvrste supstance. [0860] A mixture of intermediate 179 (350 mg) and K 2 CO 3 (102 mg, 0.74 mmol) in methanol (3 ml) was stirred at 60 °C for 1 h. The mixture was filtered and evaporated under vacuum to give the crude product. The crude product was purified by prep-HPLC (column: Waters Xbridge Prep OBD C18 150x30 mm, 5 µm, conditions: gradient water (0.05% ammonium hydroxide V/V)-ACN). The desired fractions were collected and the solvent was evaporated to give Compound 80 (113.3 mg, 94.9% yield) as a white solid.

41 41

Alternativna priprema jedinjenja 80 Alternative preparation of compound 80

[0861] [0861]

[0862] Intermedijer 529 (21 g, 40,12 mmol) rastvoren je u HCl/MeOH (250 ml). Smeša je mešana na sobnoj temperaturi tokom 2 sata. Rastvarač je koncentrovan pod vakuumom. Zatim je dodata H2O (100 ml). pH je podešen na oko 9 postepenim dodavanjem vod. Na2CO3(800 ml). Talog je uklonjen filtracijom radi dobijanja sirovog proizvoda. Sirovi proizvod je prekristalisan iz EtOH (250 ml) radi dobijanja 11,4 g jedinjenja 80 kao bele čvrste supstance. Filtrat iz prekristalizacije je koncentrovan pod vakuumom. Ovaj ostatak je dodat u EtOH (50 ml) i refluktovan tokom 3 sata. Reakcija je ohlađena, i talog je uklonjen filtracijom radi dobijanja proizvoda, 2,2 g jedinjenja 80. Filtrat iz druge prekristalizacije je koncentrovan pod vakuumom radi dobijanja još 2,2 g jedinjenja 80. [0862] Intermediate 529 (21 g, 40.12 mmol) was dissolved in HCl/MeOH (250 mL). The mixture was stirred at room temperature for 2 hours. The solvent was concentrated under vacuum. H2O (100 mL) was then added. The pH was adjusted to about 9 by gradually adding aq. Na2CO3 (800 ml). The precipitate was removed by filtration to obtain the crude product. The crude product was recrystallized from EtOH (250 mL) to give 11.4 g of compound 80 as a white solid. The filtrate from the recrystallization was concentrated under vacuum. This residue was added to EtOH (50 mL) and refluxed for 3 h. The reaction was cooled, and the precipitate was removed by filtration to give the product, 2.2 g of compound 80. The filtrate from the second recrystallization was concentrated under vacuum to give another 2.2 g of compound 80.

Primer B19 Example B19

Priprema jedinjenja 81 Preparation of compound 81

[0863] [0863]

[0864] Smeša intermedijera 184 (800 mg, 1,67 mmol) i HCl u metanolu (15 ml) mešana je na r.t. tokom 2 h. Smeša je neutralisana pomoću NH4OH. Smeša je ekstrahovana pomoću EtOAc (20 ml x 3). Organska faza je uparena, i sirovi proizvod je prečišćen pomoću prep-HPLC [0864] A mixture of intermediate 184 (800 mg, 1.67 mmol) and HCl in methanol (15 mL) was stirred at r.t. during 2 h. The mixture was neutralized with NH 4 OH. The mixture was extracted with EtOAc (20 mL x 3). The organic phase was evaporated, and the crude product was purified by prep-HPLC

41 41

(gradijent: voda (10 mM NH4HCO3)-ACN). Kombinovani rastvarač je uparen radi dobijanja jedinjenja 81 (280 mg, prinos 38%) kao bele čvrste supstance. (gradient: water (10 mM NH4HCO3)-ACN). The combined solvent was evaporated to give compound 81 (280 mg, 38% yield) as a white solid.

Primer B20 Example B20

Priprema jedinjenja 84 Preparation of compound 84

[0865] [0865]

[0866] Intermedijer 193 (110 mg, 0,23 mmol) u EtOH (3,5 ml) mešana je na r.t. Ukapavanjem je dodata 1 N HCl (2,3 ml, 2,3 mmol). Mešanje je nastavljeno još 72 h. Reakciona smeša je zatim tretirana pomoću 28% NH3u vodi (0,235 ml, 3,5 mmol). Proizvod je počeo da se taloži. Talog je uklonjen filtracijom i ispran je pomoću EtOH/H2O, odnos 9 prema 1, i osušen je, dajući jedinjenje 84 (90 mg, prinos 89%) [0866] Intermediate 193 (110 mg, 0.23 mmol) in EtOH (3.5 mL) was stirred at r.t. 1 N HCl (2.3 mL, 2.3 mmol) was added dropwise. Mixing was continued for another 72 h. The reaction mixture was then treated with 28% NH 3 in water (0.235 mL, 3.5 mmol). The product started to settle. The precipitate was removed by filtration and washed with EtOH/H2O, 9:1, and dried to give compound 84 (90 mg, 89% yield)

Primer B21 Example B21

Priprema jedinjenja 162 Preparation of compound 162

[0867] [0867]

[0868] Rastvor intermedijera 338 (520 mg, 0,96 mmol) u HCl/MeOH (4 N, 7 ml) i MeOH (2 ml) mešan je na sobnoj temperaturi tokom 1 h. Reakcija je koncentrovana. Ostatak je rastvoren u H2O (3ml) i zalužen pomoću vod. NH3.H2O. Talog je formiran i sakupljen. Čvrsta supstanca [0868] A solution of intermediate 338 (520 mg, 0.96 mmol) in HCl/MeOH (4 N, 7 mL) and MeOH (2 mL) was stirred at room temperature for 1 h. The reaction is concentrated. The residue was dissolved in H2O (3ml) and basified with aq. NH3.H2O. The precipitate was formed and collected. Solid substance

41 41

je prečišćena pomoću prep-HPLC: uslovi: A: (voda (0,05% amonijum hidroksid V/V)-B: ACN, početak B 30% kraj B 60%). Željene frakcije su sakupljene i liofilizovane radi dobijanja proizvoda (250 mg). Proizvod je dalje prečišćen pomoću prep-SFC (kolona OD (250 mm x 30 mm, 10 µm); uslovi A: 0,1% amonijum hidroksid V/V), B: EtOH; početal B 35%, kraj B 35%; protok (ml/min) 60). Željene frakcije su sakupljene i liofilizovane radi dobijanja jedinjenja 162 (206 mg, prinos 43%) kao čvrste supstance. was purified by prep-HPLC: conditions: A: (water (0.05% ammonium hydroxide V/V)-B: ACN, start B 30% end B 60%). The desired fractions were collected and lyophilized to obtain the product (250 mg). The product was further purified by prep-SFC (column OD (250 mm x 30 mm, 10 µm); conditions A: 0.1% ammonium hydroxide V/V), B: EtOH; beginning B 35%, end B 35%; flow rate (ml/min) 60). The desired fractions were collected and lyophilized to give compound 162 (206 mg, 43% yield) as a solid.

[0869] Sledeća jedinjenja su pripremljena reakcionim protokolom koji je analogan protokolu koji je korišćen za pripremu jedinjenja 162 koristeći odgovarajuće polazne supstance (Tabela 46). [0869] The following compounds were prepared by a reaction protocol analogous to that used to prepare compound 162 using the appropriate starting materials (Table 46).

Tabela 46: Table 46:

42 42

Jedinjenje Struktura Polazne supstance Compound Structure Starting substances

Jedinjenje Struktura Polazne supstance Compound Structure Starting substances

Jedinjenje Struktura Polazne supstance Compound Structure Starting substances

42 42

Jedinjenje Struktura Polazne supstance Compound Structure Starting substances

Jedinjenje Struktura Polazne supstance Compound Structure Starting substances

42 42

Jedinjenje Struktura Polazne supstance Compound Structure Starting substances

42 42

Jedinjenje Struktura Polazne supstance Compound Structure Starting substances

42 42

Jedinjenje Struktura Polazne supstance Compound Structure Starting substances

42 42

Jedinjenje Struktura Polazne supstance Compound Structure Starting substances

42 42

Jedinjenje Struktura Polazne supstance Compound Structure Starting substances

4 4

Primer B22 Example B22

Priprema jedinjenja 163 Preparation of compound 163

[0870] [0870]

[0871] Smeša intermedijera 353 (260 mg, 0,49 mmol) u HCl/MeOH (4 N, 1 ml) i MeOH (1 ml) mešana je na sobnoj temperaturi tokom 1 h. Reakcija je koncentrovana. Ostatak je zalužen pomoću NH3.H2O do pH > 8. Ostatak je prečišćen pomoću HPLC: kolona: Gemini 150 x 25 mm 5 µm; uslovi: A: voda (0,05% amonijum hidroksid V/V), B: MeCN; na početku: A (89%) i B (11%), na kraju: A (59%) i B (41%); vreme trajanja gradijenta (min) 10; 100% B vreme zadržavanja (min) 2; protok (ml/min) 25. Željene frakcije su sakupljene i koncentrovane. Ostatak je liofilizovan radi dobijanja jedinjenja 163 (93,4 mg, prinos 48,6%) kao čvrste supstance. [0871] A mixture of intermediate 353 (260 mg, 0.49 mmol) in HCl/MeOH (4 N, 1 mL) and MeOH (1 mL) was stirred at room temperature for 1 h. The reaction is concentrated. The residue was basified with NH3.H2O to pH > 8. The residue was purified by HPLC: column: Gemini 150 x 25 mm 5 µm; conditions: A: water (0.05% ammonium hydroxide V/V), B: MeCN; at the beginning: A (89%) and B (11%), at the end: A (59%) and B (41%); gradient duration (min) 10; 100% B retention time (min) 2; flow rate (ml/min) 25. Desired fractions were collected and concentrated. The residue was lyophilized to give compound 163 (93.4 mg, yield 48.6%) as a solid.

4 1 4 1

Primer B23 Example B23

Priprema jedinjenja 185 Preparation of compound 185

[0872] [0872]

[0873] Rastvor intermedijera 403 (600 mg, 1,28 mmol) u HCl/MeOH (4 N, 2,7 ml) i MeOH (1 ml) mešan je na sobnoj temperaturi tokom 4 h. Reakcija je koncentrovana. Ostatak je zalužen pomoću NH3.H2O do pH > 8. Talog je formiran i sakupljen filtracijom. Talog je ispran vodom i pomoću MTBE. Talog je liofilizovan radi dobijanja jedinjenja 185 (345 mg, prinos 61%) kao čvrste supstance. [0873] A solution of intermediate 403 (600 mg, 1.28 mmol) in HCl/MeOH (4 N, 2.7 mL) and MeOH (1 mL) was stirred at room temperature for 4 h. The reaction is concentrated. The residue was basified with NH3.H2O to pH > 8. A precipitate was formed and collected by filtration. The precipitate was washed with water and MTBE. The precipitate was lyophilized to give compound 185 (345 mg, 61% yield) as a solid.

Primer B24 Example B24

Priprema jedinjenja 187 Preparation of compound 187

[0874] [0874]

[0875] Rastvor intermedijera 365 (250 mg, 0,54 mmol) u HCl/MeOH (4 N, 1,52 ml) i MeOH (1 ml) mešan je na sobnoj temperaturi tokom 1 h. Reakcija je koncentrovana. Ostatak je zalužen sa NH3.H2O do pH > 8 i koncentrovan. Ostatak je prečišćen pomoću HPLC: kolona: Gemini 150 x 25 mm, 5 µm; uslovi: A: voda (0,05% amonijum hidroksid V/V), B: ACN); na početku: [0875] A solution of intermediate 365 (250 mg, 0.54 mmol) in HCl/MeOH (4 N, 1.52 mL) and MeOH (1 mL) was stirred at room temperature for 1 h. The reaction is concentrated. The residue was basified with NH3.H2O to pH > 8 and concentrated. The residue was purified by HPLC: column: Gemini 150 x 25 mm, 5 µm; conditions: A: water (0.05% ammonium hydroxide V/V), B: ACN); at the beginning:

4 2 4 2

A (89%) i B (11%), na kraju: A (59%) i B (41%); vreme trajanja gradijenta (min) 10; 100% B vreme zadržavanja (min) 2; protok (ml/min) 25. Željene frakcije su sakupljene i koncentrovane. Ostatak je liofilizovan radi dobijanja jedinjenja 187 (29,4 mg, prinos 13%) kao čvrste supstance. A (89%) and B (11%), at the end: A (59%) and B (41%); gradient duration (min) 10; 100% B retention time (min) 2; flow rate (ml/min) 25. Desired fractions were collected and concentrated. The residue was lyophilized to give compound 187 (29.4 mg, 13% yield) as a solid.

Primer B 25 Example B 25

Priprema jedinjenja 188 Preparation of compound 188

[0876] [0876]

[0877] Rastvor intermedijera 366 (410 mg, 0,76 mmol) u HCl/MeOH (4 N, 7 ml) i MeOH (2 ml) mešan je na sobnoj temperaturi tokom 1 h. Reakcija je koncentrovana. Ostatak je rastvoren u H2O (3ml) i zalužen pomoću vod. NH3.H2O. Talog je formiran i sakupljen. Čvrsta supstanca je prečišćena pomoću prep-HPLC (Phenomenex Gemini 150 x 25 mm, 10 µm; uslovi: A: voda (0,05% amonijum hidroksid V/V), B:ACN); na početku: A (70%) i B (30%), na kraju: A (40%) i B (60%); vreme trajanja gradijenta (min) 10; 100% B vreme zadržavanja (min) 3; protok (ml/min) 25. Željene frakcije su sakupljene i liofilizovane radi dobijanja jedinjenja 188 (131,3 mg, 34,5%) kao čvrste supstance. [0877] A solution of intermediate 366 (410 mg, 0.76 mmol) in HCl/MeOH (4 N, 7 mL) and MeOH (2 mL) was stirred at room temperature for 1 h. The reaction is concentrated. The residue was dissolved in H2O (3ml) and basified with aq. NH3.H2O. The precipitate was formed and collected. The solid was purified by prep-HPLC (Phenomenex Gemini 150 x 25 mm, 10 µm; conditions: A: water (0.05% ammonium hydroxide V/V), B: ACN); at the beginning: A (70%) and B (30%), at the end: A (40%) and B (60%); gradient duration (min) 10; 100% B retention time (min) 3; flow rate (ml/min) 25. The desired fractions were collected and lyophilized to give compound 188 (131.3 mg, 34.5%) as a solid.

Primer B26 Example B26

Priprema jedinjenja 211 Preparation of compound 211

[0878] [0878]

4 4

[0879] Kalijum karbonat (155 mg, 1,1 mmol) dodat je u intermedijer 383 (0,3 g, 0,376 mmol) u CH3CN (10 ml). Smeša je mešana na sobnoj temperaturi tokom 3 h. Smeša je uparena pod vakuumom. Ostatak je prečišćen pomoću preparativne HPLC (kolona: Waters Xbridge Prep OBD C18 150x30 mm 5 µm; uslovi: voda (0,05% amonijum hidroksid V/V)-ACN, početak: B 35%, kraj: B 65%, vreme trajanja gradijenta (min): 10, 100%B vreme zadržavanja (min): 3, protok (ml/min): 25). Kombinovani rastvarač je uparen radi dobijanja proizvoda kao bele čvrste supstance. Proizvod je prečišćen pomoću SFC razdvajanja (kolona: OJ (250 mm x 30 mm,10 um), uslovi; A: (0,1% amonijum hidroksid V/V) -B: EtOH, početak: B 50%, kraj: B 50%, protok (ml/min): 80). Kombinovani rastvarač je uparen radi dobijanja jedinjenja 211 (76 mg, prinos: 39%) kao bele čvrste supstance. [0879] Potassium carbonate (155 mg, 1.1 mmol) was added to intermediate 383 (0.3 g, 0.376 mmol) in CH 3 CN (10 mL). The mixture was stirred at room temperature for 3 h. The mixture was evaporated under vacuum. The residue was purified by preparative HPLC (column: Waters Xbridge Prep OBD C18 150x30 mm 5 µm; conditions: water (0.05% ammonium hydroxide V/V)-ACN, start: B 35%, end: B 65%, gradient time (min): 10, 100%B retention time (min): 3, flow (ml/min): 25). The combined solvent was evaporated to give the product as a white solid. The product was purified by SFC separation (column: OJ (250 mm x 30 mm, 10 µm), conditions; A: (0.1% ammonium hydroxide V/V) -B: EtOH, start: B 50%, end: B 50%, flow (ml/min): 80). The combined solvent was evaporated to give compound 211 (76 mg, yield: 39%) as a white solid.

Primer B27 Example B27

Priprema jedinjenja 253 Preparation of compound 253

[0880] Jedinjenje 253 je pripremljeno reakcionim protokolom koji je analogan protokolu korišćenom za pripremu intermedijera 382 koji je opisan u A78 (korak 1) koristeći odgovarajuće polazne supstance (Tabela 41). [0880] Compound 253 was prepared by a reaction protocol analogous to the protocol used for the preparation of intermediate 382 described in A78 (step 1) using the appropriate starting materials (Table 41).

Tabela 41: Table 41:

Primer B28 Example B28

4 4 4 4

Priprema jedinjenja 207 i 208 Preparation of compounds 207 and 208

[0881] [0881]

[0882] HCl/MeOH (1 ml, 4 mol/l) dodat je u smešu intermedijera 384 i intermedijera 385 (200 mg) u MeOH (1 ml) i mešan na sobnoj temperaturi tokom 30 min. Reakciona smeša je ukapavanjem dodata u vod. NH3.H2O (2 ml) i koncentrovana do suva pod vakuumom radi dobijanja sirovog proizvoda. Sirovi proizvod je prečišćen preparativnom tečnom hromatografijom visokih performansi na koloni: Phenomenex Gemin 150 x 25 mm 10 µm; uslovi: A: voda (0,05% amonijum hidroksid V/V), B: MeCN; na početku: A (85%) i B (15%), na kraju: A: (55%) i B (45%). Čiste frakcije su sakupljene, i rastvarač je uparen pod vakuumom. Ostatak je liofilizovan radi dobijanja jedinjenja 207 (32 mg) i jedinjenja 208 (41 mg) kao belih čvrstih supstanci. [0882] HCl/MeOH (1 ml, 4 mol/l) was added to a mixture of intermediate 384 and intermediate 385 (200 mg) in MeOH (1 ml) and stirred at room temperature for 30 min. The reaction mixture was added dropwise to water. NH3.H2O (2 ml) and concentrated to dryness under vacuum to give the crude product. The crude product was purified by preparative high-performance liquid chromatography on a column: Phenomenex Gemin 150 x 25 mm 10 µm; conditions: A: water (0.05% ammonium hydroxide V/V), B: MeCN; at the beginning: A (85%) and B (15%), at the end: A: (55%) and B (45%). The pure fractions were collected, and the solvent was evaporated under vacuum. The residue was lyophilized to give compound 207 (32 mg) and compound 208 (41 mg) as white solids.

Primer B29 Example B29

Priprema jedinjenja 215 Preparation of compound 215

[0883] [0883]

[0884] Smeša intermedijera 388 (1 g, 0,67 mmol) i K2CO3(1 g, 7,25 mmol) u CH2Cl2(10 ml) i dioksanu (10 ml) mešana je na 50°C tokom 2 sata. Smeša je filtrirana, i filtrat je koncentrovan radi dobijanja sirovog proizvoda. Sirovi proizvod je prečišćen pomoću preparativne HPLC [0884] A mixture of intermediate 388 (1 g, 0.67 mmol) and K 2 CO 3 (1 g, 7.25 mmol) in CH 2 Cl 2 (10 ml) and dioxane (10 ml) was stirred at 50 °C for 2 hours. The mixture was filtered, and the filtrate was concentrated to give the crude product. The crude product was purified by preparative HPLC

4 4

(elucioni gradijent: 0,05% NH3.H2O u CH3OH/0,05% NH3.H2O u H2O; kolona: Kromasil 150 x 25 mm, 10 µm) radi dobijanja jedinjenja 215 (102 mg, prinos 34%) kao bele čvrste supstance. (elution gradient: 0.05% NH3.H2O in CH3OH/0.05% NH3.H2O in H2O; column: Kromasil 150 x 25 mm, 10 µm) to afford compound 215 (102 mg, 34% yield) as a white solid.

Primer B30 Example B30

Priprema jedinjenja 216 Preparation of compound 216

[0885] [0885]

[0886] Smeša intermedijera 390 (300 mg, 0,60 mmol) i K2CO3(0,25 g, 1,80 mmol) u metanolu (10 ml) mešana je na 50°C tokom 2 sata. Smeša je filtrirana i koncentrovana radi dobijanja sirovog proizvoda. Sirovi proizvod je prečišćen pomoću preparativne HPLC (elucioni gradijent: 0,05% NH3.H2O u CH3OH/0,05% NH3.H2O u H2O; kolona: Kromasil 150 x 25 mm, 10 µm) radi dobijanja jedinjenja 216 (37,9 mg, prinos 15,5%) kao bele čvrste supstance. [0886] A mixture of intermediate 390 (300 mg, 0.60 mmol) and K 2 CO 3 (0.25 g, 1.80 mmol) in methanol (10 ml) was stirred at 50 °C for 2 hours. The mixture was filtered and concentrated to obtain the crude product. The crude product was purified by preparative HPLC (elution gradient: 0.05% NH3.H2O in CH3OH/0.05% NH3.H2O in H2O; column: Kromasil 150 x 25 mm, 10 µm) to afford compound 216 (37.9 mg, 15.5% yield) as a white solid.

Primer B31 Example B31

Priprema jedinjenja 198 Preparation of compound 198

[0887] [0887]

[0888] Smeša intermedijera 347 (1,2 g, 2,42 mmol) u HCl/MeOH (20 ml, 4 M) mešana je na sobnoj temperaturi tokom 2 sata. Rastvarač je koncentrovan pod vakuumom. Zatim je dodata [0888] A mixture of intermediate 347 (1.2 g, 2.42 mmol) in HCl/MeOH (20 mL, 4 M) was stirred at room temperature for 2 h. The solvent was concentrated under vacuum. Then it was added

4 4

H2O (50 ml), i pH je podešen na 9 postepenim dodavanjem čvrstog NaHCO3. Čvrsta supstanca je filtrirana i isprana pomoću H2O (100 ml x 6), metanola (100 ml x 2) i diizopropiletra (100 ml x 2). Filter pogača je osušena pod vakuumom radi dobijanja jedinjenja 198 (273,7 mg, prinos 24%) kao bele čvrste supstance. H 2 O (50 ml), and the pH was adjusted to 9 by stepwise addition of solid NaHCO 3 . The solid was filtered and washed with H 2 O (100 ml x 6), methanol (100 ml x 2) and diisopropylether (100 ml x 2). The filter cake was dried under vacuum to give compound 198 (273.7 mg, 24% yield) as a white solid.

Primer B32 Example B32

Priprema jedinjenja 199 Preparation of compound 199

[0889] [0889]

[0890] Smeša intermedijera 372 (510 mg, 0,824 mmol) u HCl/MeOH (10 ml, 4 M) mešana je na sobnoj temperaturi tokom 2 sata. Rastvarač je koncentrovan pod vakuumom. Zatim je dodata H2O (50 ml), i pH je podešen na 9 postepenim dodavanjem čvrstog NaHCO3. Zatim je dodat etil acetat (50 ml). Organski sloj je razdvojen, i vodena faza je ekstrahovana etil acetatom (50 ml x 2). Kombinovana organska faza je osušena anhidrovanim Na2SO4, filtrirana i koncentrovana pod vakuumom radi dobijanja sirovog proizvoda. Sirovi proizvod je prečišćen pomoću preparativne HPLC (kolona: Waters Xbridge Prep OBD C18 150 x 30 mm, 5 µm, uslovi: A: voda (0,05% amonijum hidroksid V/V)-B:ACN, početak: B 13%, kraj: B 43%, vreme trajanja gradijenta (min): 10, 100% B vreme zadržavanja (min): 3, protok (ml/min): 25) radi dobijanja jedinjenja 199 (84,7 mg, prinos 22%) kao bele čvrste supstance. [0890] A mixture of intermediate 372 (510 mg, 0.824 mmol) in HCl/MeOH (10 mL, 4 M) was stirred at room temperature for 2 h. The solvent was concentrated under vacuum. H 2 O (50 mL) was then added, and the pH was adjusted to 9 by stepwise addition of solid NaHCO 3 . Ethyl acetate (50 ml) was then added. The organic layer was separated, and the aqueous phase was extracted with ethyl acetate (50 ml x 2). The combined organic phase was dried over anhydrous Na 2 SO 4 , filtered and concentrated under vacuum to give the crude product. The crude product was purified by preparative HPLC (column: Waters Xbridge Prep OBD C18 150 x 30 mm, 5 µm, conditions: A: water (0.05% ammonium hydroxide V/V)-B:ACN, start: B 13%, end: B 43%, gradient time (min): 10, 100% B retention time (min): 3, flow (ml/min): 25) to give compound 199 (84.7 mg, 22% yield) as a white solid.

Primer B33 Example B33

Priprema jedinjenja 218 Preparation of compound 218

[0891] [0891]

4 4

[0892] U rastvor intermedijera 232 (500 mg, 0,677 mmol, 1,0 ekv.) u DCM-u (15 ml) dodat je BBr3(0,64 ml, 6,77 mmol, 10,0 ekv.) na -78°C u atmosferi N2. Dobijena smeša je mešana preko noći na 20°C. Čvrsta supstanca je filtrirana, isprana pomoću CH2Cl2i sakupljena radi dobijanja sirovog proizvoda. Ostatak je trituriran vodom, i pH je podešen na oko 8 postepenim dodavanjem čvrstog K2CO3. Dobijena čvrsta supstanca je filtrirana kroz levak ispran vodom (20 ml x 5) i sakupljena. Ostatak je prečišćen pomoću preparativne HPLC. (HPLC uslovi; A: voda (0,05% amonijum hidroksid V/V)-B: ACN; kolone: Gemini 150 x 25 mm, 5 µm; početak B: 9%, kraj B: 39%) radi dobijanja proizvoda jedinjenja 218 (79 mg, 0,193 mmol, prinos 29%) kao bele čvrste supstance. [0892] To a solution of intermediate 232 (500 mg, 0.677 mmol, 1.0 equiv) in DCM (15 mL) was added BBr 3 (0.64 mL, 6.77 mmol, 10.0 equiv) at -78°C under N 2 . The resulting mixture was stirred overnight at 20°C. The solid was filtered, washed with CH 2 Cl 2 and collected to give the crude product. The residue was triturated with water, and the pH was adjusted to about 8 by stepwise addition of solid K 2 CO 3 . The resulting solid was filtered through a funnel washed with water (20 ml x 5) and collected. The residue was purified by preparative HPLC. (HPLC conditions; A: water (0.05% ammonium hydroxide V/V)-B: ACN; columns: Gemini 150 x 25 mm, 5 µm; start B: 9%, end B: 39%) to give the product compound 218 (79 mg, 0.193 mmol, yield 29%) as a white solid.

Primer B34 Example B34

Priprema jedinjenja 201 Preparation of compound 201

[0893] [0893]

[0894] Intermedijer 348 (450 mg, 0,855 mmol) rastvoren je u MeOH (15 ml), dodat je HCl/MeOH (4 N, 15 ml). Reakciona smeša je mešana na sobnoj temperaturi tokom 2 sata. Rastvarač je uklonjen uparavanjem. Ostatak je trituriran sa EtOAc (100 ml) i zasićenim Na2CO3(30 ml). Organski sloj je razdvojen i ispran zasićenim vodenim rastvorom soli (30 ml), osušen iznad anhidrovanog Na2SO4, filtriran i koncentrovan. Ostatak je prečišćen pomoću prep. HPLC (Waters Xbridge Prep OBD C18150 x30 mm 5 µm, uslovi: A: voda (0,05% NH4OH [0894] Intermediate 348 (450 mg, 0.855 mmol) was dissolved in MeOH (15 mL), HCl/MeOH (4 N, 15 mL) was added. The reaction mixture was stirred at room temperature for 2 hours. The solvent was removed by evaporation. The residue was triturated with EtOAc (100 mL) and saturated Na 2 CO 3 (30 mL). The organic layer was separated and washed with brine (30 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated. The residue was purified using prep. HPLC (Waters Xbridge Prep OBD C18150 x30 mm 5 µm, conditions: A: water (0.05% NH4OH

4 4

V/V)-B: ACN, protok: 25 ml/min, gradijent od B 35% do B 65%) radi dobijanja jedinjenja 201 (148 mg, prinos 35%) kao bele čvrste supstance. V/V)-B: ACN, flow: 25 ml/min, gradient from B 35% to B 65%) to give compound 201 (148 mg, yield 35%) as a white solid.

Primer B35 Example B35

Priprema jedinjenja 200 Preparation of compound 200

[0895] [0895]

[0896] Intermedijer 373 (340 mg, 0,595 mmol) rastvoren je u MeOH (50 ml) i dodata je 4 N HCl/MeOH (10 ml). Reakciona smeša je mešana na sobnoj temperaturi tokom 2 sata. Rastvarač je uklonjen uparavanjem. Ostatak je trituriran sa EtOAc (100 ml) i zasićenim Na2CO3(30 ml), razdvojeni organski sloj je ispran zasićenim vodenim rastvorom soli (30 ml), osušen iznad anhidrovanog Na2SO4, filtriran i koncentrovan. Ostatak je prečišćen pomoću prep. HPLC (Waters Xbridge Prep OBD C18150 x30 mm 5 µm, uslovi; A: voda (0,05% NH4OH V/V)- B: ACN, protok: 25 ml/min, gradijent od B 35% do B 65%) radi dobijanja jedinjenja 200 (135 mg, prinos 46%) kao bele čvrste supstance. [0896] Intermediate 373 (340 mg, 0.595 mmol) was dissolved in MeOH (50 mL) and 4 N HCl/MeOH (10 mL) was added. The reaction mixture was stirred at room temperature for 2 hours. The solvent was removed by evaporation. The residue was triturated with EtOAc (100 mL) and saturated Na2CO3 (30 mL), the separated organic layer was washed with brine (30 mL), dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified using prep. HPLC (Waters Xbridge Prep OBD C18150 x30 mm 5 µm, conditions; A: water (0.05% NH4OH V/V)- B: ACN, flow: 25 ml/min, gradient from B 35% to B 65%) to afford compound 200 (135 mg, yield 46%) as a white solid.

Primer B36 Example B36

Priprema jedinjenja 204 Preparation of compound 204

[0897] [0897]

4 4

[0898] Rastvor intermedijera 374 (350 mg, 0,73 mmol) u HCl/MeOH (4 M, 10 ml) mešan je na sobnoj temperaturi tokom 2 sata. Smeša je zalužena sa NH3.H2O (20 ml) do pH > 7. Rastvor je ispran vodom (60 ml) i ekstrahovan pomoću EtOAc (80 ml x 3). Kombinovani organski slojevi su isprani zasićenim vodenim rastvorom soli (80 ml), osušeni (Na2SO4), filtrirani i koncentrovani pod vakuumom radi dobijanja sirovog proizvoda kao smeđe čvrste supstance. Sirovi proizvod je prečišćen pomoću HPLC (kolona: Waters Xbridge Prep OBD C18150 x 30 mm 5 µm; uslovi; A: voda (0,05% amonijum hidroksid V/V)-B: ACN; početak B: 25%; kraj B: 55%; vreme trajanja gradijenta (min): 10; 100% B vreme zadržavanja (min): 3; protok (ml/min): 25) radi dobijanja jedinjenja 204 (102,9 mg, prinos 32%) kao bele čvrste supstance. [0898] A solution of intermediate 374 (350 mg, 0.73 mmol) in HCl/MeOH (4 M, 10 mL) was stirred at room temperature for 2 hours. The mixture was basified with NH 3 .H 2 O (20 mL) to pH > 7. The solution was washed with water (60 mL) and extracted with EtOAc (80 mL x 3). The combined organic layers were washed with brine (80 mL), dried (Na 2 SO 4 ), filtered and concentrated in vacuo to afford the crude product as a brown solid. The crude product was purified by HPLC (column: Waters Xbridge Prep OBD C18150 x 30 mm 5 µm; conditions; A: water (0.05% ammonium hydroxide V/V)-B: ACN; start B: 25%; end B: 55%; gradient time (min): 10; 100% B retention time (min): 3; flow rate (ml/min): 25) to give compound 204 (102.9 mg, yield 32%) as a white solid.

Primer B37 Example B37

Priprema jedinjenja 203 Preparation of compound 203

[0899] [0899]

[0900] Rastvor intermedijera 350 (300 mg, 0,61 mmol) u HCl/CH3OH (4 mol/l, 10 ml) mešan je na sobnoj temperaturi tokom 2 sata. Smeša je zalužena sa NH3.H2O (8 ml) do pH > 7. Rastvor je tretiran vodom (100 ml) i ekstrahovan etil acetatom (150 ml x 3). Kombinovani organski slojevi su isprani zasićenim vodenim rastvorom soli (100 ml), osušeni (Na2SO4), filtrirani i koncentrovani pod vakuumom radi dobijanja sirovog proizvoda kao smeđe čvrste supstance. Sirovi proizvod je prečišćen pomoću HPLC (kolona: Waters Xbridge Prep OBD C18150 x 30 mm, 5 µm; uslovi; A: voda (0,05% amonijum hidroksid V/V)-B: ACN; početak B: 25%;kraj B: 55%; vreme trajanja gradijenta (min): 10; 100% B vreme zadržavanja (min): 3; protok (ml/min): 25) radi dobijanja jedinjenja 203 (129,8 mg, prinos 47%) kao bele čvrste supstance. [0900] A solution of intermediate 350 (300 mg, 0.61 mmol) in HCl/CH 3 OH (4 mol/l, 10 ml) was stirred at room temperature for 2 hours. The mixture was basified with NH 3 .H 2 O (8 ml) to pH > 7. The solution was treated with water (100 ml) and extracted with ethyl acetate (150 ml x 3). The combined organic layers were washed with brine (100 mL), dried (Na 2 SO 4 ), filtered and concentrated in vacuo to afford the crude product as a brown solid. The crude product was purified by HPLC (column: Waters Xbridge Prep OBD C18150 x 30 mm, 5 µm; conditions; A: water (0.05% ammonium hydroxide V/V)-B: ACN; start B: 25%; end B: 55%; gradient time (min): 10; 100% B retention time (min): 3; flow (ml/min): 25) to give compound 203 (129.8 mg, yield 47%) as a white solid.

44 44

Primer B38 Example B38

Priprema jedinjenja 202 Preparation of compound 202

[0901] [0901]

[0902] Rastvor intermedijera 349 (350 mg, 0,734 mmol) u HCl/CH3OH (4 M, 10 ml) mešan je na sobnoj temperaturi tokom 2 sata. Smeša je zalužena sa NH3.H2O (10 ml) do pH > 7. Rastvor je ispran vodom (100 ml) i ekstrahovan etil acetatom (150 ml x 3). Kombinovani organski slojevi su isprani zasićenim vodenim rastvorom soli (100 ml), osušeni (Na2SO4), filtrirani i koncentrovani pod vakuumom radi dobijanja sirovog proizvoda kao smeđe čvrste supstance. Sirovi proizvod je prečišćen pomoću HPLC radi dobijanja jedinjenja 202 (149 mg, prinos 46%) kao bele čvrste supstance. [0902] A solution of intermediate 349 (350 mg, 0.734 mmol) in HCl/CH 3 OH (4 M, 10 mL) was stirred at room temperature for 2 hours. The mixture was basified with NH 3 .H 2 O (10 ml) to pH > 7. The solution was washed with water (100 ml) and extracted with ethyl acetate (150 ml x 3). The combined organic layers were washed with brine (100 mL), dried (Na 2 SO 4 ), filtered and concentrated in vacuo to afford the crude product as a brown solid. The crude product was purified by HPLC to give compound 202 (149 mg, 46% yield) as a white solid.

Primer B39 Example B39

Priprema jedinjenja 219 Preparation of compound 219

[0903] [0903]

[0904] U rastvor intermedijera 422 (600 mg, 0,80 mmol) u DCM-u (11 ml) ukapavanjem je dodata TFA (12 ml, 163 mmol) u atmosferi N2na 0°C. Reakciona smeša je mešana na 0°C tokom 30 minuta, zatim je dodata H2O (3 ml). Reakciona smeša je mešana na sobnoj temperaturi preko noći. Rastvarač je uklonjen pod vakuumom. Ostatak je rastvoren u vodi (30 ml) i pH je podešen na 8, i zatim je filtriran. Čvrsta supstanca je sakupljena, osušena pod vakuumom radi dobijanja jedinjenja 219 (326 mg, prinos 86,5%) kao bele čvrste supstance. [0904] To a solution of intermediate 422 (600 mg, 0.80 mmol) in DCM (11 ml) was added dropwise TFA (12 ml, 163 mmol) under N 2 at 0°C. The reaction mixture was stirred at 0 °C for 30 min, then H 2 O (3 mL) was added. The reaction mixture was stirred at room temperature overnight. The solvent was removed under vacuum. The residue was dissolved in water (30 ml) and the pH adjusted to 8, and then filtered. The solid was collected, dried under vacuum to afford compound 219 (326 mg, 86.5% yield) as a white solid.

Primer B40 Example B40

Priprema jedinjenja 220 Preparation of compound 220

[0905] [0905]

[0906] U rastvor intermedijera 424 (1 g, 1,20 mmol) u DCM-u (10 ml) ukapavanjem je dodata TFA (10 ml, 135 mmol) u atmosferi N2na 0°C. Reakciona smeša je mešana na 0°C tokom 30 minuta, zatim je dodata H2O (3 ml). Reakciona smeša je mešana na sobnoj temperaturi tokom 4 sata. Rastvarač je uklonjen pod vakuumom. Ostatak je rastvoren u MeOH (10 ml) i podešen na pH 8, zatim filtriran, i filtrat je koncentrovan radi dobijanja sirovog proizvoda. Sirovi proizvod je prečišćen pomoću HPLC kolone: DuraShell 150 x 25 mm, 5 µm; uslovi: A: voda (0,05% NH4OH V/V), B: MeOH; na početku: A (60%) i B (40%), na kraju: A (30%) i B (70%); vreme trajanja gradijenta (min) 10; 100% B vreme zadržavanja (min) 3; protok (ml/min) 25 radi dobijanja jedinjenja 220 (106 mg, prinos 19%) kao bele čvrste supstance. [0906] To a solution of intermediate 424 (1 g, 1.20 mmol) in DCM (10 ml) was added dropwise TFA (10 ml, 135 mmol) under N 2 at 0°C. The reaction mixture was stirred at 0 °C for 30 min, then H 2 O (3 mL) was added. The reaction mixture was stirred at room temperature for 4 hours. The solvent was removed under vacuum. The residue was dissolved in MeOH (10 mL) and adjusted to pH 8, then filtered, and the filtrate was concentrated to give the crude product. The crude product was purified using an HPLC column: DuraShell 150 x 25 mm, 5 µm; conditions: A: water (0.05% NH4OH V/V), B: MeOH; at the beginning: A (60%) and B (40%), at the end: A (30%) and B (70%); gradient duration (min) 10; 100% B retention time (min) 3; flow rate (ml/min) 25 to afford compound 220 (106 mg, 19% yield) as a white solid.

Primer B42 Example B42

Priprema jedinjenja 221 Preparation of compound 221

[0907] [0907]

[0908] Smeša intermedijera 426 (150 mg, 0,123 mmol) i kalijum karbonata (51 mg, 0,369 mmol) u metanolu (3 ml) mešana je na 60°C tokom 1 h. Smeša je filtrirana i filtrat je uparen pod vakuumom radi dobijanja sirovog proizvoda kao čvrste supstance. Ovaj ostatak je prečišćen pomoću preparativne HPLC (kolona: Waters Xbridge Prep OBD C18150 x 30 mm, 5 µm, uslovi; A: voda (0,05% amonijum hidroksid V/V) -B: ACN, početak: B 13%, kraj: B 43%, vreme trajanja gradijenta (min): 10, 100% B vreme zadržavanja (min): 3, protok (ml/min): 25). Kombinovani rastvarači su upareni radi dobijanja jedinjenja 221 (39 mg) kao bele čvrste supstance. [0908] A mixture of intermediate 426 (150 mg, 0.123 mmol) and potassium carbonate (51 mg, 0.369 mmol) in methanol (3 mL) was stirred at 60 °C for 1 h. The mixture was filtered and the filtrate was evaporated under vacuum to give the crude product as a solid. This residue was purified by preparative HPLC (column: Waters Xbridge Prep OBD C18150 x 30 mm, 5 µm, conditions; A: water (0.05% ammonium hydroxide V/V) -B: ACN, start: B 13%, end: B 43%, gradient time (min): 10, 100% B retention time (min): 3, flow (ml/min): 25). The combined solvents were evaporated to give compound 221 (39 mg) as a white solid.

C. Konverzija jedinjenja C. Compound conversion

Primer C1 Example C1

Priprema jedinjenja 217 Preparation of compound 217

[0909] [0909]

[0910] U rastvor jedinjenja 2 (1,6 g, 2,88 mmol, 1,0 ekv.), 2,4,6-trimetil-1,3,5,2,4,6-trioksatriborinana (0,72 g, 5,76 mmol, 2,0 ekv.) i K2CO3(0,796 g, 5,76 mmol, 2,0 ekv.) u dioksanu/H2O, odnos 10/1 (30 ml) dodat je Pd(dppf)Cl2(210 mg, 0,288 mmol, 0,1 ekv.). Dobijena smeša je mešana na 90°C u atmosferi N2tokom 16 sati. Dobijena čvrsta supstanca je uklonjena filtracijom. Filtrat je koncentrovan. Ostatak je trituriran sa vodom (30 ml) i dodat je DCM (30 ml). Čvrsta supstanca je istaložena iz reakcije. Dobijena čvrsta supstanca je filtrirana [0910] To a solution of compound 2 (1.6 g, 2.88 mmol, 1.0 eq.), 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (0.72 g, 5.76 mmol, 2.0 eq.) and K 2 CO 3 (0.796 g, 5.76 mmol, 2.0 eq.) in to dioxane/H2O, 10/1 ratio (30 mL) was added Pd(dppf)Cl2 (210 mg, 0.288 mmol, 0.1 eq.). The resulting mixture was stirred at 90°C in an N2 atmosphere for 16 hours. The resulting solid was removed by filtration. The filtrate was concentrated. The residue was triturated with water (30 ml) and DCM (30 ml) was added. A solid precipitated out of the reaction. The resulting solid was filtered

44 44

radi dobijanja sirovog proizvoda. Ostatak je prečišćen hromatografijom na koloni (gradijent: petrol etar/etil acetat/MeOH odnos 20/1/0 do 0/20/1). Frakcije proizvoda su sakupljene, i rastvarač je uparen radi dobijanja proizvoda kao čvrste supstance. Proizvod je prečišćen putem preparativne HPLC (HPLC uslovi: A: voda (0,05% amonijum hidroksid v/v)- B: ACN; kolona: Gemini 150 x 25mm, 5 µm; početak B: 15%, kraj B: 45%) radi dobijanja proizvoda jedinjenja 217 (300 mg, 0,73 mmol, prinos 25%) kao bele čvrste supstance. in order to obtain a raw product. The residue was purified by column chromatography (gradient: petroleum ether/ethyl acetate/MeOH ratio 20/1/0 to 0/20/1). The product fractions were collected, and the solvent was evaporated to give the product as a solid. The product was purified by preparative HPLC (HPLC conditions: A: water (0.05% ammonium hydroxide v/v)- B: ACN; column: Gemini 150 x 25mm, 5 µm; start B: 15%, end B: 45%) to give the product compound 217 (300 mg, 0.73 mmol, yield 25%) as a white solid.

Primer C2 Example C2

Priprema jedinjenja 212 Preparation of compound 212

[0911] [0911]

[0912] U rastvor jedinjenja 2 (1 g, 1,8 mmol) u dioksanu (40 ml) i H2O (10 ml) dodat je kalijum izopropenil trifluorborat (319 mg, 2,16 mmol) i K3PO4(764 mg, 3,6 mmol) na sobnoj temperaturi. U prethodni rastvor je dodat 1,1'-bis(di-terc-butilfosfino)ferocen paladijum dihlorid (58 mg, 0,09 mmol) u atmosferi azota. Reakciona smeša je mešana na 80°C u atmosferi azota preko noći. Smeša je ekstrahovana etil acetatom, organski slojevi su kombinovani i koncentrovani pod vakuumom radi dobijanja sirovog proizvoda. [0912] To a solution of compound 2 (1 g, 1.8 mmol) in dioxane (40 ml) and H 2 O (10 ml) was added potassium isopropenyl trifluoroborate (319 mg, 2.16 mmol) and K 3 PO 4 (764 mg, 3.6 mmol) at room temperature. To the previous solution was added 1,1'-bis(di-tert-butylphosphino)ferrocene palladium dichloride (58 mg, 0.09 mmol) under a nitrogen atmosphere. The reaction mixture was stirred at 80°C under nitrogen overnight. The mixture was extracted with ethyl acetate, the organic layers were combined and concentrated in vacuo to give the crude product.

[0913] Ovaj sirovi proizvod je prečišćen pomoću preparativne HPLC (elucioni gradijent: 0,05% NH3.H2O u CH3CN/0,05% NH3.H2O u H2O; kolona: DuraShell 150 x 25 mm, 5 µm). Kombinovani rastvarač je uparen radi dobijanja željenog proizvoda kao bele čvrste supstance proizvoda (300 mg, 35% prinos).100 mg proizvoda je prečišćeno putem SFC razdvajanja (AD (250 mm x 30 mm,10 µm)). Kombinovani rastvarači su upareni pod vakuumom radi dobijanja željenog proizvoda kao bele čvrste supstance jedinjenja 212 (71,9 mg). [0913] This crude product was purified by preparative HPLC (elution gradient: 0.05% NH3.H2O in CH3CN/0.05% NH3.H2O in H2O; column: DuraShell 150 x 25 mm, 5 µm). The combined solvent was evaporated to give the desired product as a white product solid (300 mg, 35% yield). 100 mg of the product was purified via SFC separation (AD (250 mm x 30 mm, 10 µm)). The combined solvents were evaporated under vacuum to give the desired product as a white solid compound 212 (71.9 mg).

Primer C3 Example C3

Priprema jedinjenja 213 Preparation of compound 213

[0914] [0914]

[0915] Pd/C (20 mg) dodat je u smešu jedinjenja 253 (200 mg, 0,429 mmol) u MeOH (20 ml). Smeša je hidrogenovana na 25°C tokom 24 h u atmosferi H2. Smeša je filtrirana i uparena pod vakuumom radi dobijanja sirovog proizvoda. Sirovi proizvod je prečišćen pomoću preparativne HPLC (elucioni gradijent: 0,05% NH3.H2O u CH3CN/0,05% NH3.H2O u H2O; kolona: Waters Xbridge Prep OBD C18150 x 30 mm, 5 mm). Kombinovani rastvarač je uparen radi dobijanja jedinjenja 213 kao bele čvrste supstance (132 mg, 73% prinos). [0915] Pd/C (20 mg) was added to a mixture of compound 253 (200 mg, 0.429 mmol) in MeOH (20 mL). The mixture was hydrogenated at 25°C for 24 h under an H2 atmosphere. The mixture was filtered and evaporated under vacuum to give the crude product. The crude product was purified by preparative HPLC (elution gradient: 0.05% NH3.H2O in CH3CN/0.05% NH3.H2O in H2O; column: Waters Xbridge Prep OBD C18150 x 30 mm, 5 mm). The combined solvent was evaporated to give compound 213 as a white solid (132 mg, 73% yield).

[0916] Sledeća jedinjenja su pripremljena reakcionim protokolom koji je analogan protokolu koji je korišćen za pripremu jedinjenja 213 koristeći odgovarajuće polazne supstance (Tabela 47). [0916] The following compounds were prepared by a reaction protocol analogous to that used to prepare compound 213 using the appropriate starting materials (Table 47).

Tabela 47: Table 47:

Analitički deo Analytical part

NMR NMR

44 44

[0917] Za određeni broj jedinjenja i ilustrativnih primera,<1>H NMR spektar je snimljen na uređaju Bruker DPX-360 na 360 MHz, Bruker Avance 600 na 600 MHz, Bruker Avance 400 na 400 MHz, ili na Varian 400MR spektrometru na 400MHz. Kao rastvarači su korišćeni HLOROFORM-d (deuterisani hloroform, CDCl3), metanol-d4ili DMSO-d6(deuterisani DMSO, dimetil-d6 sulfoksid). Hemijski pomaci (δ) zabeleženi su kao delovi na milion (ppm) u odnosu na tetrametilsilan (TMS), koji je korišćen kao interni standard. [0917] For a number of compounds and illustrative examples,<1>H NMR spectra were recorded on a Bruker DPX-360 at 360 MHz, a Bruker Avance 600 at 600 MHz, a Bruker Avance 400 at 400 MHz, or a Varian 400MR spectrometer at 400 MHz. CHLOROFORM-d (deuterated chloroform, CDCl3), methanol-d4 or DMSO-d6 (deuterated DMSO, dimethyl-d6 sulfoxide) were used as solvents. Chemical shifts (δ) were reported as parts per million (ppm) relative to tetramethylsilane (TMS), which was used as an internal standard.

[0918] Jed.217:<1>H NMR (400 MHz, DMSO-d6) δ ppm 2.44 (s, 3 H) 4.21 - 4.34 (m, 3 H) 4.34 - 4.43 (m, 1 H) 4.50 (q, J=5.7 Hz, 1 H) 5.37 (d, J=5.0 Hz, 1 H) 5.44 (d, J=6.3 Hz, 1 H) 6.17 (d, J=5.5 Hz, 1 H) 6.61 (d, J=3.8 Hz, 1 H) 7.01 (br s, 2 H) 7.27 (dd, J=8.8, 2.5 Hz, 1 H) 7.37 (d, J=3.8 Hz, 1 H) 7.41 (d, J=2.3 Hz, 1 H) 7.81 (d, J=9.0 Hz, 1 H) 8.05 (br s, 1 H) 8.07 (s, 1 H) 8.70 (d, J=2.0 Hz, 1 H). [0918] Jed.217:<1>H NMR (400 MHz, DMSO-d6) δ ppm 2.44 (s, 3 H) 4.21 - 4.34 (m, 3 H) 4.34 - 4.43 (m, 1 H) 4.50 (q, J=5.7 Hz, 1 H) 5.37 (d, J=5.0 Hz, 1 H) 5.44 (d, J=6.3 Hz, 1 H) 6.17 (d, J=5.5 Hz, 1 H) 6.61 (d, J=3.8 Hz, 1 H) 7.01 (br s, 2 H) 7.27 (dd, J=8.8, 2.5 Hz, 1 H) 7.37 (d, J=3.8 Hz, 1 H) 7.41 (d, J=2.3 Hz, 1 H) 7.81 (d, J=9.0 Hz, 1 H) 8.05 (br s, 1 H) 8.07 (s, 1 H) 8.70 (d, J=2.0 Hz, 1 H).

[0919] Jed.218:<1>H NMR (400 MHz, DMSO-d6) δ ppm 4.14 - 4.34 (m, 4 H) 4.48 (q, J=5.7 Hz, 1 H) 5.36 (d, J=5.0 Hz, 1 H) 5.44 (d, J=6.3 Hz, 1 H) 6.15 (d, J=5.5 Hz, 1 H) 6.33 (br s, 2 H) 6.58 (d, J=8.8 Hz, 1 H) 6.61 (d, J=3.8 Hz, 1 H) 6.83 (dd, J=8.7, 2.4 Hz, 1 H) 6.91 (d, J=2.3 Hz, 1 H) 7.02 (br s, 2 H) 7.35 (d, J=3.8 Hz, 1 H) 7.53 (d, J=8.8 Hz, 1 H) 7.79 (d, J=8.8 Hz, 1 H) 8.07 (s, 1 H). [0919] Jed.218:<1>H NMR (400 MHz, DMSO-d6) δ ppm 4.14 - 4.34 (m, 4 H) 4.48 (q, J=5.7 Hz, 1 H) 5.36 (d, J=5.0 Hz, 1 H) 5.44 (d, J=6.3 Hz, 1 H) 6.15 (d, J=5.5 Hz, 1 H) 6.33 (br s, 2 H) 6.58 (d, J=8.8 Hz, 1 H) 6.61 (d, J=3.8 Hz, 1 H) 6.83 (dd, J=8.7, 2.4 Hz, 1 H) 6.91 (d, J=2.3 Hz, 1 H) 7.02 (br s, 2 H) 7.35 (d, J=3.8 Hz, 1 H) 7.53 (d, J=8.8 Hz, 1 H) 7.79 (d, J=8.8 Hz, 1 H) 8.07 (s, 1 H).

[0920] Jed.74:<1>H NMR (600 MHz, DMSO-d6) δ ppm 0.24 - 0.27 (m, 2 H) 0.45 - 0.48 (m, 2 H) 1.08 - 1.14 (m, 1 H) 1.52 (dt, J=12.4, 10.3 Hz, 1 H) 1.67 - 1.74 (m, 1 H) 1.84 - 1.92 (m, 1 H) 1.96 (ddt, J=13.0, 9.3, 6.4, 6.4 Hz, 1 H) 2.25 (dt, J=12.7, 7.9 Hz, 1 H) 2.65 - 2.72 (m, 1 H) 2.72 - 2.79 (m, 1 H) 3.26 (dd, J=6.5, 5.6 Hz, 2 H) 3.75 (q, J=4.9 Hz, 1 H) 4.21 (dt, J=7.6, 6.2 Hz, 1 H) 4.63 (d, J=4.8 Hz, 1 H) 4.77 (d, J=6.3 Hz, 1 H) 4.81 (dt, J=10.5, 8.0 Hz, 1 H) 6.55 (d, J=3.5 Hz, 1 H) 6.72 (d, J=8.9 Hz, 1 H) 6.91 (br s, 2 H) 6.99 - 7.03 (m, 2 H) 7.26 (d, J=3.5 Hz, 1 H) 7.33 (s, 1 H) 7.50 (d, J=8.1 Hz, 1 H) 7.76 (d, J=8.8 Hz, 1 H) 8.04 (s, 1 H). [0920] Jed.74:<1>H NMR (600 MHz, DMSO-d6) δ ppm 0.24 - 0.27 (m, 2 H) 0.45 - 0.48 (m, 2 H) 1.08 - 1.14 (m, 1 H) 1.52 (dt, J=12.4, 10.3 Hz, 1 H) 1.67 - 1.74 (m, 1 H) 1.84 - 1.92 (m, 1 H) 1.96 (ddt, J=13.0, 9.3, 6.4, 6.4 Hz, 1 H) 2.25 (dt, J=12.7, 7.9 Hz, 1 H) 2.65 - 2.72 (m, 1 H) 2.72 - 2.79 (m, 1 H) 3.26 (dd, J=6.5, 5.6 Hz, 2 H) 3.75 (q, J=4.9 Hz, 1 H) 4.21 (dt, J=7.6, 6.2 Hz, 1 H) 4.63 (d, J=4.8 Hz, 1 H) 4.77 (d, J=6.3 Hz, 1 H) 4.81 (dt, J=10.5, 8.0 Hz, 1 H) 6.55 (d, J=3.5 Hz, 1 H) 6.72 (d, J=8.9 Hz, 1 H) 6.91 (br s, 2 H) 6.99 - 7.03 (m, 2 H) 7.26 (d, J=3.5 Hz, 1 H) 7.33 (s, 1 H) 7.50 (d, J=8.1 Hz, 1 H) 7.76 (d, J=8.8 Hz, 1 H) 8.04 (s, 1 H).

[0921] Jed.129:<1>H NMR (360 MHz, DMSO-d6) δ ppm 1.53 (dt, J=12.3, 10.2 Hz, 1 H) 1.69 -1.81 (m, 1 H) 1.82 - 1.93 (m, 1 H) 1.95 - 2.05 (m, 1 H) 2.25 (dt, J=12.4, 7.9 Hz, 1 H) 2.78 -2.93 (m, 2 H) 3.76 (q, J=5.0 Hz, 1 H) 4.21 (q, J=5.9 Hz, 1 H) 4.66 (d, J=4.8 Hz, 1 H) 4.73 -4.86 (m, 2 H) 6.55 (d, J=3.3 Hz, 1 H) 6.95 (br s, 2 H) 7.27 (d, J=3.7 Hz, 1 H) 7.59 (dd, J=8.4, 1.8 Hz, 1 H) 7.87 (s, 1 H) 7.91 (d, J=8.4 Hz, 1 H) 8.03 (s, 1 H) 8.68 (d, J=2.2 Hz, 1 H) 8.91 (d, J=2.6 Hz, 1 H). [0921] Jed.129:<1>H NMR (360 MHz, DMSO-d6) δ ppm 1.53 (dt, J=12.3, 10.2 Hz, 1 H) 1.69 -1.81 (m, 1 H) 1.82 - 1.93 (m, 1 H) 1.95 - 2.05 (m, 1 H) 2.25 (dt, J=12.4, 7.9 Hz, 1 H) 2.78 -2.93 (m, 2 H) 3.76 (q, J=5.0 Hz, 1 H) 4.21 (q, J=5.9 Hz, 1 H) 4.66 (d, J=4.8 Hz, 1 H) 4.73 -4.86 (m, 2 H) 6.55 (d, J=3.3 Hz, 1 H) 6.95 (br s, 2 H) 7.27 (d, J=3.7 Hz, 1 H) 7.59 (dd, J=8.4, 1.8 Hz, 1 H) 7.87 (s, 1 H) 7.91 (d, J=8.4 Hz, 1 H) 8.03 (s, 1 H) 8.68 (d, J=2.2 Hz, 1 H) 8.91 (d, J=2.6 Hz, 1 H).

44 44

[0922] Jed.130:<1>H NMR (400 MHz, DMSO-d6) δ ppm 4.22 - 4.39 (m, 3 H) 4.59 (q, J=5.0 Hz, 1 H) 5.49 (br d, J=4.5 Hz, 1 H) 5.60 (d, J=6.0 Hz, 1 H) 6.29 (d, J=5.5 Hz, 1 H) 6.64 (m, J=9.0 Hz, 2 H) 6.78 (d, J=3.8 Hz, 1 H) 6.90 (dd, J=8.7, 1.9 Hz, 1 H) 6.97 (d, J=1.5 Hz, [0922] Jed.130:<1>H NMR (400 MHz, DMSO-d6) δ ppm 4.22 - 4.39 (m, 3 H) 4.59 (q, J=5.0 Hz, 1 H) 5.49 (br d, J=4.5 Hz, 1 H) 5.60 (d, J=6.0 Hz, 1 H) 6.29 (d, J=5.5 Hz, 1 H) 6.64 (m, J=9.0 Hz, 2 H) 6.78 (d, J=3.8 Hz, 1 H) 6.90 (dd, J=8.7, 1.9 Hz, 1 H) 6.97 (d, J=1.5 Hz,

[0923] 1 H) 7,58 (d, J=8,5 Hz, 1 H) 7,87 (d, J=9,0 Hz, 1 H) 7,97 (d, J=4,0 Hz, 1 H) 8,69 (s, 1 H). [0923] 1 H) 7.58 (d, J=8.5 Hz, 1 H) 7.87 (d, J=9.0 Hz, 1 H) 7.97 (d, J=4.0 Hz, 1 H) 8.69 (s, 1 H).

[0924] Jed.176:<1>H NMR (400 MHz, Metanol-d4) δ ppm 2.32 - 2.45 (m, 1 H) 2.48 - 2.62 (m, 1 H) 2.65 - 2.83 (m, 2 H) 3.01 - 3.12 (m, 1 H) 3.45 (s, 3 H) 3.49 - 3.63 (m, 2 H) 3.69 (d, J=4.8 Hz, 3 H) 4.53 - 4.61 (m, 1 H) 5.05 - 5.11 (m, 1 H) 5.51 (d, J=4.8 Hz, 1 H) 5.60 (d, J=6.3 Hz, 1 H) 5.70 - 5.81 (m, 1 H) 7.47 (d, J=8.8 Hz, 1 H) 7.50 (d, J=3.8 Hz, 1 H) 7.73 (br q, J=5.0 Hz, 1 H) 7.84 (dd, J=8.0, 1.5 Hz, 1 H) 8.17 (br s, 1 H) 8.32 (d, J=8.0 Hz, 1 H) 8.53 (d, J=3.5 Hz, 1 H) 8.58 (d, J=8.8 Hz, 1 H) 9.43 (s, 1 H). [0924] Jed.176:<1>H NMR (400 MHz, Methanol-d4) δ ppm 2.32 - 2.45 (m, 1 H) 2.48 - 2.62 (m, 1 H) 2.65 - 2.83 (m, 2 H) 3.01 - 3.12 (m, 1 H) 3.45 (s, 3 H) 3.49 - 3.63 (m, 2 H) 3.69 (d, J=4.8 Hz, 3 H) 4.53 - 4.61 (m, 1 H) 5.05 - 5.11 (m, 1 H) 5.51 (d, J=4.8 Hz, 1 H) 5.60 (d, J=6.3 Hz, 1 H) 5.70 - 5.81 (m, 1 H) 7.47 (d, J=8.8 Hz, 1 H) 7.50 (d, J=3.8 Hz, 1 H) 7.73 (br q, J=5.0 Hz, 1 H) 7.84 (dd, J=8.0, 1.5 Hz, 1 H) 8.17 (br s, 1 H) 8.32 (d, J=8.0 Hz, 1 H) 8.53 (d, J=3.5 Hz, 1 H) 8.58 (d, J=8.8 Hz, 1 H) 9.43 (s, 1 H).

[0925] Jed.80:<1>H NMR (600 MHz, DMSO-d6) δ ppm 1.50 - 1.56 (m, 1 H) 1.68 - 1.75 (m, 1 H) 1.85 - 1.92 (m, 1 H) 1.96 (ddt, J=13.0, 9.0, 6.5, 6.5 Hz, 1 H) 2.25 (dt, J=12.7, 7.9 Hz, 1 H) 2.69 - 2.80 (m, 2 H) 3.76 (br t, J=4.7 Hz, 1 H) 4.21 (dd, J=7.6, 6.0 Hz, 1 H) 4.57 (br s, 1 H) 4.72 (br s, 1 H) 4.80 (dt, J=10.5, 7.9 Hz, 1 H) 6.50 (br s, 2 H) 6.59 (d, J=3.5 Hz, 1 H) 7.07 (br s, 2 H) 7.12 (dd, J=8.2, 1.6 Hz, 1 H) 7.29 (d, J=3.6 Hz, 1 H) 7.34 (s, 1 H) 7.58 (d, J=8.1 Hz, 1 H) 8.07 (s, 1 H) 8.31 (s, 1 H). [0925] Jed.80:<1>H NMR (600 MHz, DMSO-d6) δ ppm 1.50 - 1.56 (m, 1 H) 1.68 - 1.75 (m, 1 H) 1.85 - 1.92 (m, 1 H) 1.96 (ddt, J=13.0, 9.0, 6.5, 6.5 Hz, 1 H) 2.25 (dt, J=12.7, 7.9 Hz, 1 H) 2.69 - 2.80 (m, 2 H) 3.76 (br t, J=4.7 Hz, 1 H) 4.21 (dd, J=7.6, 6.0 Hz, 1 H) 4.57 (br s, 1 H) 4.72 (br s, 1 H) 4.80 (dt, J=10.5, 7.9 Hz, 1 H) 6.50 (br s, 2 H) 6.59 (d, J=3.5 Hz, 1 H) 7.07 (br s, 2 H) 7.12 (dd, J=8.2, 1.6 Hz, 1 H) 7.29 (d, J=3.6 Hz, 1 H) 7.34 (s, 1 H) 7.58 (d, J=8.1 Hz, 1 H) 8.07 (s, 1 H) 8.31 (s, 1 H).

[0926] Jed.185:<1>H NMR (400 MHz, DMSO-d6) δ ppm 2.96 (br d, J=3.5 Hz, 3 H) 4.16 - 4.36 (m, 4 H) 4.44 - 4.55 (m, 1 H) 5.38 (br d, J=5.3 Hz, 1 H) 5.47 (br d, J=6.2 Hz, 1 H) 6.16 (d, J=5.7 Hz, 1 H) 6.63 (d, J=4.0 Hz, 1 H) 6.70 (br d, J=9.3 Hz, 1 H) 6.89 - 6.97 (m, 1 H) 7.05 -7.23 (m, 3 H) 7.37 (d, J=3.5 Hz, 1 H) 7.63 (br d, J=9.3 Hz, 1 H) 7.84 - 7.95 (m, 1 H) 8.09 (s, 1 H). [0926] Jed.185:<1>H NMR (400 MHz, DMSO-d6) δ ppm 2.96 (br d, J=3.5 Hz, 3 H) 4.16 - 4.36 (m, 4 H) 4.44 - 4.55 (m, 1 H) 5.38 (br d, J=5.3 Hz, 1 H) 5.47 (br d, J=6.2 Hz, 1 H) 6.16 (d, J=5.7 Hz, 1 H) 6.63 (d, J=4.0 Hz, 1 H) 6.70 (br d, J=9.3 Hz, 1 H) 6.89 - 6.97 (m, 1 H) 7.05 -7.23 (m, 3 H) 7.37 (d, J=3.5 Hz, 1 H) 7.63 (No d, J=9.3 Hz, 1 H) 7.84 - 7.95 (m, 1 H) 8.09 (s, 1 H).

[0927] Jed.75:<1>H NMR (400 MHz, DMSO-d6) δ ppm 1.45 - 1.59 (m, 1 H) 1.65 - 1.77 (m, 1 H) 1.83 - 2.02 (m, 2 H) 2.25 (dt, J=12.5, 7.9 Hz, 1 H) 2.63 - 2.83 (m, 2 H) 3.72 - 3.89 (m, 3 H) 4.16 - 4.24 (m, 1 H) 4.64 (d, J=4.8 Hz, 1 H) 4.77 (d, J=6.3 Hz, 1 H) 4.79 - 4.84 (m, 1 H) 6.22 (tt, J=56.7, 4.1 Hz, 1 H) 6.54 (d, J=3.5 Hz, 1 H) 6.78 (d, J=8.8 Hz, 1 H) 6.91 (br s, 2 H) 7.09 (dd, J=8.2, 1.6 Hz, 1 H) 7.26 (d, J=3.5 Hz, 1 H) 7.36 (t, J=6.0 Hz, 1 H) 7.40 (br s, 1 H) 7.57 (d, J=8.0 Hz, 1 H) 7.87 (d, J=8.8 Hz, 1 H) 8.03 (s, 1 H). Co.81:<1>H NMR (400 MHz, DMSO-d6) δ ppm 1.42 - 1.60 (m, 1 H) 1.62 - 1.77 (m, 1 H) 1.81 - 2.00 (m, 2 H) 2.24 (dt, J=12.7, 7.8 Hz, [0927] Jed.75:<1>H NMR (400 MHz, DMSO-d6) δ ppm 1.45 - 1.59 (m, 1 H) 1.65 - 1.77 (m, 1 H) 1.83 - 2.02 (m, 2 H) 2.25 (dt, J=12.5, 7.9 Hz, 1 H) 2.63 - 2.83 (m, 2 H) 3.72 - 3.89 (m, 3 H) 4.16 - 4.24 (m, 1 H) 4.64 (d, J=4.8 Hz, 1 H) 4.77 (d, J=6.3 Hz, 1 H) 4.79 - 4.84 (m, 1 H) 6.22 (tt, J=56.7, 4.1 Hz, 1 H) 6.54 (d, J=3.5 Hz, 1 H) 6.78 (d, J=8.8 Hz, 1 H) 6.91 (br s, 2 H) 7.09 (dd, J=8.2, 1.6 Hz, 1 H) 7.26 (d, J=3.5 Hz, 1 H) 7.36 (t, J=6.0 Hz, 1 H) 7.40 (br s, 1 H) 7.57 (d, J=8.0 Hz, 1 H) 7.87 (d, J=8.8 Hz, 1 H) 8.03 (s, 1 H). Co.81:<1>H NMR (400 MHz, DMSO-d6) δ ppm 1.42 - 1.60 (m, 1 H) 1.62 - 1.77 (m, 1 H) 1.81 - 2.00 (m, 2 H) 2.24 (dt, J=12.7, 7.8 Hz,

44 44

1 H) 2.64 - 2.83 (m, 2 H) 3.70 - 3.79 (m, 1 H) 4.16 - 4.25 (m, 1 H) 4.62 (br d, J=4.9 Hz, 1 H) 4.71 - 4.87 (m, 2 H) 6.54 (d, J=3.5 Hz, 1 H) 6.65 (br s, 2 H) 6.90 (br s, 2 H) 7.12 (br d, J=7.5 Hz, 1 H) 7.25 (d, J=3.5 Hz, 1 H) 7.34 (s, 1 H) 7.58 (d, J=8.4 Hz, 1 H) 8.03 (s, 1 H) 8.14 (s, 1 H). 1 H) 2.64 - 2.83 (m, 2 H) 3.70 - 3.79 (m, 1 H) 4.16 - 4.25 (m, 1 H) 4.62 (br d, J=4.9 Hz, 1 H) 4.71 - 4.87 (m, 2 H) 6.54 (d, J=3.5 Hz, 1 H) 6.65 (br s, 2 H) 6.90 (br s, 2 H) 7.12 (br d, J=7.5 Hz, 1 H) 7.25 (d, J=3.5 Hz, 1 H) 7.34 (s, 1 H) 7.58 (d, J=8.4 Hz, 1 H) 8.03 (s, 1 H) 8.14 (s, 1 H).

[0928] Jed.151:<1>H NMR (400 MHz, DMSO-d6) δ ppm 1.45 - 1.57 (m, 1 H) 1.62 - 1.77 (m, 1 H) 1.82 - 2.01 (m, 2 H) 2.25 (dt, J=12.4, 7.9 Hz, 1 H) 2.65 - 2.82 (m, 2 H) 3.75 (q, J=4.8 Hz, 1 H) 4.20 (dt, J=7.6, 6.2 Hz, 1 H) 4.26 - 4.39 (m, 2 H) 4.64 (d, J=4.8 Hz, 1 H) 4.73 - 4.87 (m, 2 H) 6.54 (d, J=3.5 Hz, 1 H) 6.82 (d, J=8.8 Hz, 1 H) 6.91 (br s, 2 H) 7.12 (dd, J=8.0, 1.5 Hz, 1 H) 7.26 (d, J=3.5 Hz, 1 H) 7.42 (s, 1 H) 7.54 (br t, J=6.4 Hz, 1 H) 7.59 (d, J=8.0 Hz, 1 H) 7.91 (d, J=8.9 Hz, 1 H) 8.03 (s, 1 H). [0928] Jed.151:<1>H NMR (400 MHz, DMSO-d6) δ ppm 1.45 - 1.57 (m, 1 H) 1.62 - 1.77 (m, 1 H) 1.82 - 2.01 (m, 2 H) 2.25 (dt, J=12.4, 7.9 Hz, 1 H) 2.65 - 2.82 (m, 2 H) 3.75 (q, J=4.8 Hz, 1 H) 4.20 (dt, J=7.6, 6.2 Hz, 1 H) 4.26 - 4.39 (m, 2 H) 4.64 (d, J=4.8 Hz, 1 H) 4.73 - 4.87 (m, 2 H) 6.54 (d, J=3.5 Hz, 1 H) 6.82 (d, J=8.8 Hz, 1 H) 6.91 (br s, 2 H) 7.12 (dd, J=8.0, 1.5 Hz, 1 H) 7.26 (d, J=3.5 Hz, 1 H) 7.42 (s, 1 H) 7.54 (br t, J=6.4 Hz, 1 H) 7.59 (d, J=8.0 Hz, 1 H) 7.91 (d, J=8.9 Hz, 1 H) 8.03 (s, 1 H).

[0929] Jed.152:<1>H NMR (400 MHz, DMSO-d6) δ ppm 0.39 - 0.62 (m, 2 H) 0.67 - 0.84 (m, 2 H) 1.46 - 1.62 (m, 1 H) 1.64 - 1.78 (m, 1 H) 1.82 - 2.02 (m, 2 H) 2.25 (dt, J=12.6, 8.0 Hz, 1 H) 2.63 - 2.83 (m, 3 H) 3.70 - 3.79 (m, 1 H) 4.15 - 4.25 (m, 1 H) 4.63 (d, J=4.9 Hz, 1 H) 4.73 -4.86 (m, 2 H) 6.54 (d, J=3.5 Hz, 1 H) 6.75 (br d, J=8.8 Hz, 1 H) 6.90 (br s, 2 H) 7.05 (dd, J=8.2, 1.5 Hz, 1 H) 7.13 (br d, J=2.6 Hz, 1 H) 7.26 (d, J=3.5 Hz, 1 H) 7.37 (br s, 1 H) 7.54 (d, J=7.9 Hz, 1 H) 7.84 (d, J=8.8 Hz, 1 H) 8.03 (s, 1 H). [0929] Jed.152:<1>H NMR (400 MHz, DMSO-d6) δ ppm 0.39 - 0.62 (m, 2 H) 0.67 - 0.84 (m, 2 H) 1.46 - 1.62 (m, 1 H) 1.64 - 1.78 (m, 1 H) 1.82 - 2.02 (m, 2 H) 2.25 (dt, J=12.6, 8.0 Hz, 1 H) 2.63 - 2.83 (m, 3 H) 3.70 - 3.79 (m, 1 H) 4.15 - 4.25 (m, 1 H) 4.63 (d, J=4.9 Hz, 1 H) 4.73 -4.86 (m, 2 H) 6.54 (d, J=3.5 Hz, 1 H) 6.75 (br d, J=8.8 Hz, 1 H) 6.90 (br s, 2 H) 7.05 (dd, J=8.2, 1.5 Hz, 1 H) 7.13 (br d, J=2.6 Hz, 1 H) 7.26 (d, J=3.5 Hz, 1 H) 7.37 (br s, 1 H) 7.54 (d, J=7.9 Hz, 1 H) 7.84 (d, J=8.8 Hz, 1 H) 8.03 (s, 1 H).

[0930] Jed.146:<1>H NMR (400 MHz, DMSO-d6) δ ppm 1.38 - 1.63 (m, 5 H) 1.65 - 1.75 (m, 3 H) 1.82 - 2.04 (m, 4 H) 2.25 (dt, J=12.5, 7.9 Hz, 1 H) 2.63 - 2.80 (m, 2 H) 3.71 - 3.78 (m, 1 H) 4.14 - 4.25 (m, 1 H) 4.33 (dq, J=13.6, 6.7 Hz, 1 H) 4.63 (d, J=4.9 Hz, 1 H) 4.73 - 4.86 (m, 2 H) 6.54 (d, J=3.1 Hz, 1 H) 6.66 (d, J=8.8 Hz, 1 H) 6.76 - 6.97 (m, 3 H) 7.01 (dd, J=7.9, 1.3 Hz, 1 H) 7.26 (d, J=3.5 Hz, 1 H) 7.32 (s, 1 H) 7.49 (d, J=8.4 Hz, 1 H) 7.74 (d, J=8.8 Hz, 1 H) 8.03 (s, 1 H). [0930] Jed.146:<1>H NMR (400 MHz, DMSO-d6) δ ppm 1.38 - 1.63 (m, 5 H) 1.65 - 1.75 (m, 3 H) 1.82 - 2.04 (m, 4 H) 2.25 (dt, J=12.5, 7.9 Hz, 1 H) 2.63 - 2.80 (m, 2 H) 3.71 - 3.78 (m, 1 H) 4.14 - 4.25 (m, 1 H) 4.33 (dq, J=13.6, 6.7 Hz, 1 H) 4.63 (d, J=4.9 Hz, 1 H) 4.73 - 4.86 (m, 2 H) 6.54 (d, J=3.1 Hz, 1 H) 6.66 (d, J=8.8 Hz, 1 H) 6.76 - 6.97 (m, 3 H) 7.01 (dd, J=7.9, 1.3 Hz, 1 H) 7.26 (d, J=3.5 Hz, 1 H) 7.32 (s, 1 H) 7.49 (d, J=8.4 Hz, 1 H) 7.74 (d, J=8.8 Hz, 1 H) 8.03 (s, 1 H).

[0931] Jed.76:<1>H NMR (400 MHz, DMSO-d6) δ ppm 1.43 - 1.57 (m, 1 H) 1.62 - 1.76 (m, 1 H) 1.79 - 2.01 (m, 2 H) 2.18 - 2.29 (m, 1 H) 2.65 - 2.79 (m, 2 H) 3.70 - 3.78 (m, 1 H) 4.14 -4.25 (m, 1 H) 4.63 (br d, J=4.9 Hz, 1 H) 4.73 - 4.86 (m, 2 H) 6.42 (br s, 2 H) 6.54 (br d, J=3.5 Hz, 1 H) 6.69 (br d, J=8.8 Hz, 1 H) 6.92 (br s, 2 H) 7.05 (br d, J=8.4 Hz, 1 H) 7.26 (br d, J=3.5 Hz, 1 H) 7.28 (br s, 1 H) 7.54 (br d, J=7.9 Hz, 1 H) 7.84 (br d, J=8.8 Hz, 1 H) 8.02 (s, 1 H). [0931] Jed.76:<1>H NMR (400 MHz, DMSO-d6) δ ppm 1.43 - 1.57 (m, 1 H) 1.62 - 1.76 (m, 1 H) 1.79 - 2.01 (m, 2 H) 2.18 - 2.29 (m, 1 H) 2.65 - 2.79 (m, 2 H) 3.70 - 3.78 (m, 1 H) 4.14 -4.25 (m, 1 H) 4.63 (br d, J=4.9 Hz, 1 H) 4.73 - 4.86 (m, 2 H) 6.42 (br s, 2 H) 6.54 (br d, J=3.5 Hz, 1 H) 6.69 (br d, J=8.8 Hz, 1 H) 6.92 (br s, 2 H) 7.05 (br d, J=8.4 Hz, 1 H) 7.26 (br d, J=3.5 Hz, 1 H) 7.28 (br s, 1 H) 7.54 (br d, J=7.9 Hz, 1 H) 7.84 (br d, J=8.8 Hz, 1 H) 8.02 (s, 1 H).

[0932] Jed.121:<1>H NMR (400 MHz, DMSO-d6) δ ppm 1.56 - 1.68 (m, 1 H) 1.69 - 1.82 (m, 1 H) 1.84 - 2.05 (m, 2 H) 2.24 - 2.37 (m, 1 H) 2.63 - 2.81 (m, 2 H) 2.88 (d, J=4.4 Hz, 3 H) 3.73 [0932] Jed.121:<1>H NMR (400 MHz, DMSO-d6) δ ppm 1.56 - 1.68 (m, 1 H) 1.69 - 1.82 (m, 1 H) 1.84 - 2.05 (m, 2 H) 2.24 - 2.37 (m, 1 H) 2.63 - 2.81 (m, 2 H) 2.88 (d, J=4.4 Hz, 3 H) 3.73

44 44

- 3.81 (m, 1 H) 4.25 - 4.35 (m, 1 H) 4.73 (d, J=4.4 Hz, 1 H) 4.86 (d, J=6.6 Hz, 1 H) 4.93 - 5.04 (m, 1 H) 6.66 (d, J=8.8 Hz, 1 H) 6.69 (d, J=3.5 Hz, 1 H) 6.87 - 6.94 (m, 1 H) 7.03 (br dd, J=7.9, 1.3 Hz, 1 H) 7.37 (s, 1 H) 7.51 (d, J=8.4 Hz, 1 H) 7.77 (br d, J=8.8 Hz, 1 H) 7.95 (d, J=4.0 Hz, 1 H) 8.63 (s, 1 H). - 3.81 (m, 1 H) 4.25 - 4.35 (m, 1 H) 4.73 (d, J=4.4 Hz, 1 H) 4.86 (d, J=6.6 Hz, 1 H) 4.93 - 5.04 (m, 1 H) 6.66 (d, J=8.8 Hz, 1 H) 6.69 (d, J=3.5 Hz, 1 H) 6.87 - 6.94 (m, 1 H) 7.03 (br dd, J=7.9, 1.3 Hz, 1 H) 7.37 (s, 1 H) 7.51 (d, J=8.4 Hz, 1 H) 7.77 (br d, J=8.8 Hz, 1 H) 7.95 (d, J=4.0 Hz, 1 H) 8.63 (s, 1H).

[0933] Jed.113:<1>H NMR (400 MHz, DMSO-d6) δ ppm 1.48 - 1.58 (m, 1 H) 1.70 - 1.80 (m, 1 H) 1.82 - 1.94 (m, 1 H) 1.95 - 2.04 (m, 1 H) 2.25 (dt, J=12.5, 8.1 Hz, 1 H) 2.46 (s, 3 H) 2.75 -2.90 (m, 2 H) 3.71 - 3.80 (m, 1 H) 4.20 (br dd, J=14.1, 6.2 Hz, 1 H) 4.65 (d, J=5.3 Hz, 1 H) 4.73 - 4.86 (m, 2 H) 6.54 (d, J=3.5 Hz, 1 H) 6.92 (br s, 2 H) 7.26 (d, J=3.5 Hz, 1 H) 7.47 (dd, J=8.4, 1.8 Hz, 1 H) 7.76 - 7.85 (m, 2 H) 8.02 (s, 1 H) 8.07 (br s, 1 H) 8.72 (d, J=2.2 Hz, 1 H). [0933] Jed.113:<1>H NMR (400 MHz, DMSO-d6) δ ppm 1.48 - 1.58 (m, 1 H) 1.70 - 1.80 (m, 1 H) 1.82 - 1.94 (m, 1 H) 1.95 - 2.04 (m, 1 H) 2.25 (dt, J=12.5, 8.1 Hz, 1 H) 2.46 (s, 3 H) 2.75 -2.90 (m, 2 H) 3.71 - 3.80 (m, 1 H) 4.20 (br dd, J=14.1, 6.2 Hz, 1 H) 4.65 (d, J=5.3 Hz, 1 H) 4.73 - 4.86 (m, 2 H) 6.54 (d, J=3.5 Hz, 1 H) 6.92 (br s, 2 H) 7.26 (d, J=3.5 Hz, 1 H) 7.47 (dd, J=8.4, 1.8 Hz, 1 H) 7.76 - 7.85 (m, 2 H) 8.02 (s, 1 H) 8.07 (br s, 1 H) 8.72 (d, J=2.2 Hz, 1 H).

OR (optička rotacija) OR (optical rotation)

[0934] Optička rotacija je izmerena na Perkin-Elmer 341 polarimetru sa natrijumskom lampom (korišćena talasna dužina svetlosti je 589 nm (natrijumova D linija)). ('T' označava temperaturu). [0934] Optical rotation was measured on a Perkin-Elmer 341 polarimeter with a sodium lamp (the wavelength of light used was 589 nm (sodium D line)). ('T' stands for temperature).

Tabela: Vrednosti optičke rotacije za enantiomerno čista jedinjenja Table: Optical rotation values for enantiomerically pure compounds

Jed. αD (°) Talasna dužina Koncentraci a Rastvarač T Eat. αD (°) Wavelength Concentrations a Solvent T

44 44

LCMS (tečna hromatografija/masena spektrometrija) LCMS (Liquid Chromatography/Mass Spectrometry)

[0935] Tečna hromatografija visokih performansi (HPLC) obavljena je koristeći LC pumpu, niz dioda (DAD) ili UV detektor i kolonu, kako je navedeno za odgovarajuće postupke. Po potrebi, uključeni su dodatni detektori (vidite tabelu postupaka ispod). [0935] High performance liquid chromatography (HPLC) was performed using an LC pump, diode array (DAD) or UV detector and column, as indicated for the respective procedures. If necessary, additional detectors are included (see procedure table below).

[0936] Protok sa kolone je doveden do masenog spektrometra (MS) koji je konfigurisan sa izvorom jona pri atmosferskom pritisku. Stručnjak će umeti da podesi parametre (npr. raspon skeniranja, vreme zadržavanja...) kako bi se dobili joni koji omogućavaju identifikaciju nominalne monoizotopske molekulske težine (Mm) jedinjenja. Prikupljanje podataka je obavljeno odgovarajućim softverom. Jedinjenja su opisana preko svojih eksperimentalnih retencionih vremena (Rt) i jona. Ako nije drugačije naznačeno u tabeli podataka, prijavljeni molekulski jon odgovara [M+H]<+>(protonovani molekul) i/ili [M-H]<->(deprotonovani molekul). [0936] The flow from the column was fed to a mass spectrometer (MS) configured with an ion source at atmospheric pressure. One of skill in the art will be able to adjust the parameters (eg scan range, retention time...) to obtain ions that allow identification of the nominal monoisotopic molecular weight (Mm) of the compound. Data collection was done with appropriate software. Compounds are described by their experimental retention times (Rt) and ions. Unless otherwise indicated in the data table, the molecular ion reported corresponds to [M+H]<+>(protonated molecule) and/or [M-H]<->(deprotonated molecule).

4 4

U slučaju da jedinjenje nije bilo moguće neposredno jonizovati, naznačen je tip adukta (tj. In case the compound could not be directly ionized, the type of adduct is indicated (i.e.

[M+NH4]<+>, [M+HCOO]-, itd...). Za molekule sa više izotopskih obrazaca (Br. Cl), prijavljena vrednost je ona koja je dobijena za najmanju izotopsku masu. Svi podaci su dobijeni uz nesigurnost eksperimenta uobičajeno povezanu sa korišćenim postupkom. [M+NH4]<+>, [M+HCOO]-, etc...). For molecules with multiple isotopic patterns (Br. Cl), the value reported is that obtained for the lowest isotopic mass. All data are obtained with the experimental uncertainty normally associated with the procedure used.

[0937] U nastavku ovog teksta, „SQD“ označava jedan kvadrupolni detektor, „MSD“ maseno selektivni detektor, „RT“ sobnu temperaturu, „BEH“ hibrid premošćeni etilsiloksan/silicijum dioksid, „DAD“ detektor sa nizom fotodioda, „HSS“ silicijum dioksid velike jačine, „Q-Tof“ kvadrupolna masena spektrometrija vremena prolaska, „CLND“ hemiluminescentni azotni detektor, „ELSD“ uparavajući svetlosno skenirajući detektor, [0937] Hereinafter, "SQD" stands for single quadrupole detector, "MSD" mass selective detector, "RT" room temperature, "BEH" hybrid bridged ethylsiloxane/silica, "DAD" photodiode array detector, "HSS" high power silicon dioxide, "Q-Tof" quadrupole time-of-flight mass spectrometry, "CLND" chemiluminescent nitrogen detector, "ELSD" pairing light scanning detector,

Tabela: Šifre LCMS postupka (protok izražen u ml/min; temperatura kolone (T) u °C; trajanje procesa u minutima). Table: LCMS procedure codes (flow expressed in ml/min; column temperature (T) in °C; process duration in minutes).

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[0938] Tabela: Jed. br. znači jedinjenje broj; retenciono vreme (Rt) u min; n.d. znači nije određeno. [0938] Table: Eq. no. means compound number; retention time (Rt) in min; n.d. means it is not determined.

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EKSPERIMENTALNE PROCEDURE in vitro test (test 1a i 1b) EXPERIMENTAL PROCEDURES in vitro test (test 1a and 1b)

[0939] Reagensi. PRMT5-MEP50 enzim je kupljen od laboratorije Charles River (Argenta). Enzimski kompleks je proizveden u ćelijama insekta (Sf9) koje su istovremeno inficirane sa dva bakulovirusa. Jedan virus eksprimira humani PRMT5 kompletne dužine sa Flag-oznakom na N-terminusu, drugi virus eksprimira MEP50 kompletne dužine sa His6-TEV cepanjem na N-terminusu. Protein je afinitetno prečišćen koristeći anti-Flag (M2) perlice eluirane 3xFLAG peptidom, nakon čega je usledio His-Select eluiran 0,5 M imidazolom. Eluirani protein je zatim dijaliziran naspram tris-puferovanog fiziološkog rastvora (TBS) (pH 8,0) koji sadrži 20% glicerol i 3 mM ditiotreitol (DTT). [0939] Reagents. PRMT5-MEP50 enzyme was purchased from Charles River Laboratories (Argenta). The enzyme complex was produced in insect cells (Sf9) that were simultaneously infected with two baculoviruses. One virus expresses full-length human PRMT5 with a Flag-tagged N-terminus, the other virus expresses full-length MEP50 with His6-TEV cleavage at the N-terminus. The protein was affinity purified using anti-Flag (M2) beads eluted with 3xFLAG peptide, followed by His-Select eluted with 0.5 M imidazole. The eluted protein was then dialyzed against Tris-buffered saline (TBS) (pH 8.0) containing 20% glycerol and 3 mM dithiothreitol (DTT).

[0940] Neoznačeni humani rekombinantni histon H2A kompletne dužine (ostaci 1-130, Genbank pristupni br. NM_021052, MW = 14,1 kDa) eksprimiran u E. coli kupljen je od Reaction Biology Corporation, kat. br. HMT-11-146. Reagensi koji su korišćeni za pravljenje reakcionog pufera ili zaustavljanje reakcije su kupljeni, uključujući Tris bazu (Sigma kat. br. [0940] Full-length untagged human recombinant histone H2A (residues 1-130, Genbank accession no. NM_021052, MW = 14.1 kDa) expressed in E. coli was purchased from Reaction Biology Corporation, cat. no. HMT-11-146. Reagents used to make the reaction buffer or stop the reaction were purchased, including Tris base (Sigma cat. no.

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T-1503), NaCl (Sigma kat. br. RGF-3270), MgCl2(Sigma kat. br. M0250), DTT (Invitrogen kat. br.15508-013) i mravlju kiselinu (Riedel deHaen, kat. br.33015) T-1503), NaCl (Sigma cat. no. RGF-3270), MgCl2 (Sigma cat. no. M0250), DTT (Invitrogen cat. no. 15508-013) and formic acid (Riedel deHaen, cat. no. 33015)

[0941] Test visokopropusnim masenim spektrometrom PRMT5 katalizuje sekvencijalno metilovanje terminalnih atoma azota na guanidinskim grupama argininskih ostataka u proteinima koristeći kosupstrat S-adenozil-L-metionin (AdoMet, SAM), dajući mono-metil (MMA), simetrični-dimetil arginin (sDMA) i S-adenozil-L-homocistein (AdoHcy, SAH). Enzimska aktivnost je određena prateći nastanak proizvoda SAH koristeći visokopropusnu masenu spektrometriju (Agilent Rapidfire 300 sistem povezan sa Sciex 4000 serijom QTrap® triple-quad MS/MS). Reakcioni pufer je bio 20 mM Tris-HCl, pH 8,5, 50 mM NaCl, 5 mM MgCl2i 1 mM DTT. Reakciona aktivnost je prekinuta koristeći 1% mravlju kiselinu (finalna koncentracija). Studije inhibicije. Studije IC50su obavljene koristeći dozne serije sa jedanaest tačaka načinjene za svako jedinjenje serijskim razblažienjem 1:2 u dimetil sulfoksidu (DMSO), gde je 12. tačka DMSO kontrola. Jedinjenja su prvo tačkasto naneta na ploče, nakon čega je dodata smeša rastvora 2 µM SAM i 0,6 µM H2A (histon H2A). Ista zapremina enzimskog rastvora je dodata radi započinjanja enzimskih reakcija. Finalne koncentracije u reakciji su na 1 µM SAM, 0,3 µM H2A i 10 nM enzima (test 1a) ili 1,25 nM enzima (test 1b). Reakcija je inkubirana na 30°C tokom 60 minuta (min) kada je korišćen 10 nM enzim, i tokom 120 min kada je korišćen 1,25 nM enzim. Nakon toga, reakcija je prekinuta dodatkom mravlje kiseline do finalne koncentracije od 1%. Inhibicija nastanka SAH u prisustvu jedinjenja izračunata je kao procenat kontrole u odnosu na neinhibiranu reakciju u funkciji koncentracije inhibitora. Podaci su prikazani na sledeći način: [0941] High-throughput mass spectrometer assay PRMT5 catalyzes the sequential methylation of terminal nitrogen atoms on the guanidine groups of arginine residues in proteins using the cosubstrate S-adenosyl-L-methionine (AdoMet, SAM), yielding mono-methyl (MMA), symmetric-dimethyl arginine (sDMA) and S-adenosyl-L-homocysteine (AdoHcy, SAH). Enzyme activity was determined by monitoring the formation of SAH products using high-throughput mass spectrometry (Agilent Rapidfire 300 system coupled to a Sciex 4000 series QTrap® triple-quad MS/MS). The reaction buffer was 20 mM Tris-HCl, pH 8.5, 50 mM NaCl, 5 mM MgCl2, and 1 mM DTT. The reaction activity was stopped using 1% formic acid (final concentration). Inhibition studies. IC50 studies were performed using eleven-point dose series made for each compound by a 1:2 serial dilution in dimethyl sulfoxide (DMSO), where the 12th point is the DMSO control. Compounds were first spotted on the plates, after which a mixture of 2 µM SAM and 0.6 µM H2A (histone H2A) solution was added. The same volume of enzyme solution was added to initiate the enzyme reactions. The final concentrations in the reaction are at 1 µM SAM, 0.3 µM H2A and 10 nM enzyme (assay 1a) or 1.25 nM enzyme (assay 1b). The reaction was incubated at 30°C for 60 minutes (min) when 10 nM enzyme was used, and for 120 min when 1.25 nM enzyme was used. After that, the reaction was terminated by the addition of formic acid to a final concentration of 1%. The inhibition of the formation of SAH in the presence of the compound was calculated as a percentage of the control in relation to the uninhibited reaction as a function of the concentration of the inhibitor. The data is presented as follows:

gde je IC50koncentracija inhibitora (ista jedinica kao X) na 50% inhibicije, a h je nagib krive. Y je procenat inhibicije, X je log koncentracije jedinjenja. Dno i vrh su zaravni u istim jedinicama kao Y. where IC50 is the inhibitor concentration (same unit as X) at 50% inhibition and h is the slope of the curve. Y is the percent inhibition, X is the log concentration of the compound. Bottom and top are flush in the same units as Y.

EKSPERIMENTALNI POSTUPAK PD test (test 2) EXPERIMENTAL PROCEDURE PD test (test 2)

Reagensi Reagents

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[0942] A549 ćelije (ATCC, kat. br. CCL-185) uzgajane su u Dulbekovom modifikovanom Iglovom medijumu (DMEM) (Sigma, kat. br. D5796), uz dodatak 10% fetalnog goveđeg seruma (FCS) (HyClone™, kat. br. SV30160.03), 100 mM natrijum piruvata (Sigma, kat. br. S8636), 200 mM L-glutamina (Sigma, kat. br. G7513) i 50 mg/ml gentamicina (Gibco, kat. br. [0942] A549 cells (ATCC, Cat. No. CCL-185) were grown in Dulbecco's Modified Needle Medium (DMEM) (Sigma, Cat. No. D5796), supplemented with 10% fetal bovine serum (FCS) (HyClone™, Cat. No. SV30160.03), 100 mM sodium pyruvate (Sigma, Cat. No. S8636), 200 mM L-glutamine (Sigma, cat. no. G7513) and 50 mg/ml gentamicin (Gibco, cat. no.

15750-037). 15750-037).

[0943] Reagensi koji su korišćeni za pufere su nabavljeni: Dulbekov fiziološki rastvor puferovan fosfatom (DPBS) bez Ca/Mg (Sigma, kat. br. D8537), fiziološki rastvor puferovan fosfatom (PBS) 10X (Roche, kat. br.11 666 789 001), 10% rastvor formalina (Sigma, HT50-1-128-4L), 100% metanol (Sigma, kat. br. 32213-2.5L), Triton X-100 (Acros, kat. br. [0943] Reagents used for buffers were purchased: Ca/Mg-free Dulbecco's phosphate-buffered saline (DPBS) (Sigma, cat. no. D8537), phosphate-buffered saline (PBS) 10X (Roche, cat. no. 11 666 789 001), 10% formalin solution (Sigma, HT50-1-128-4L), 100% methanol (Sigma, cat. no. 32213-2.5L), Triton X-100 (Acros, cat. no.

215680010), albumin goveđeg seruma (BSA) (Sigma, kat. br. A2153), Alexa fluor 488 kozje antizečje antitelo (Life Technologies, kat. br. A11034), HCS CellMask tamnocrvena boja (Life Technologies, kat. br. H32721), Hehstova boja (Life Technologies, kat. br. 33258), antidimetil-arginin, sym (SYM10) antitelo (Millipore, 07-412). 215680010), bovine serum albumin (BSA) (Sigma, cat. no. A2153), Alexa Fluor 488 goat anti-rabbit antibody (Life Technologies, cat. no. A11034), HCS CellMask dark red stain (Life Technologies, cat. no. H32721), Hoechst stain (Life Technologies, cat. no. 33258), antidimethyl-arginine, sym. (SYM10) antibody (Millipore, 07-412).

Imunohistohemijski postupak Immunohistochemical procedure

[0944] Ćelije su zasejane sa 400 ćelija/40 µl/bunarčiću crnih ploča sa providnim dnom sa 384 bunarčića (Perkin Elmer) i preko noći inkubirane na 37°C, 5% CO2. Studije IC50su obavljene koristeći dozne serije sa devet tačaka u rasponu od 10 µM do 1 µM za svako jedinjenje.80 nl odgovarajućeg razblaženja jedinjenja je dodato koristeći Labcyte POD 810 (Labcyte) sa finalnom koncentracijom DSMO od 0,2% u ćelijskoj kulturi. Nakon perioda inkubacije od 48 h na 37°C i 5% CO2, ćelije su fiksirane u 10% rastvoru formalina tokom 15 min na sobnoj temperaturi i 20 min u ledeno hladnom metanolu, nakon čega su isprane 3x u DPBS-u. Nakon toga, ćelije su blokirane tokom 1 h u puferu za blokiranje (PBS 1% BSA i 0,5% Triton X-100) i inkubirane preko noći na 4°C sa SYM10 antitelom razblaženim 1/2000 u puferu za blokiranje. Ćelije su 3x isprane puferom za ispiranje (PBS 0,1% Triton X-100) i inkubirane sa Alexa Fluor 488 kozjim antizečjim antitelom razblaženim 1/200 u puferu za blokiranje tokom 1 h na sobnoj temperaturi. Nakon toga, isprane su 3x puferom za ispiranje i inkubirane tokom 30 min na sobnoj temperaturi sa PBS-om koji sadrži razblaženje 1/5000 Hehstove boje i razblaženje 1/5000 HCS CellMask tamnocrvene boje. Nakon poslednjeg ispiranja PBS-om, ploče su snimljene koristeći 10xW sočiva Opera® sistema (Perkin Elmer Life Sciences) koristeći sledeće postavke (vrednosti u nm): [0944] Cells were seeded at 400 cells/40 µl/well of 384-well clear bottom black plates (Perkin Elmer) and incubated overnight at 37°C, 5% CO 2 . IC50 studies were performed using nine-point dose series ranging from 10 µM to 1 µM for each compound. 80 nl of the appropriate compound dilution was added using a Labcyte POD 810 (Labcyte) with a final DSMO concentration of 0.2% in cell culture. After an incubation period of 48 h at 37°C and 5% CO2, cells were fixed in 10% formalin solution for 15 min at room temperature and 20 min in ice-cold methanol, after which they were washed 3x in DPBS. Subsequently, cells were blocked for 1 h in blocking buffer (PBS 1% BSA and 0.5% Triton X-100) and incubated overnight at 4°C with SYM10 antibody diluted 1/2000 in blocking buffer. Cells were washed 3x with wash buffer (PBS 0.1% Triton X-100) and incubated with Alexa Fluor 488 goat anti-rabbit antibody diluted 1/200 in blocking buffer for 1 h at room temperature. Afterwards, they were washed 3x with wash buffer and incubated for 30 min at room temperature with PBS containing a 1/5000 dilution of Hecht's stain and a 1/5000 dilution of HCS CellMask Dark Red. After a final PBS wash, plates were imaged using a 10xW Opera® system lens (Perkin Elmer Life Sciences) using the following settings (values in nm):

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Analize: Analysis:

[0945] Inhibicija nuklearnog simetričnog argininskog dimetilovanja u prisustvu jedinjenja (% dejstva) izračunata je kao „medijana nuklearnog intenziteta SYM10“ / „medijanu citoplazmatskog intenziteta SYM10“, normalizovana pomoću sledeće jednačine: [0945] Inhibition of nuclear symmetric arginine dimethylation in the presence of compound (% effect) was calculated as "median nuclear SYM10 intensity" / "median cytoplasmic SYM10 intensity", normalized using the following equation:

[0946] U prethodnim jednačinama, koriste se sledeći nazivi promenljivih: [0946] In the previous equations, the following variable names are used:

[0947] U prethodnim jednačinama, sledeće kontrole su korišćene za normalizaciju: Niska kontrola: minimalni nivo simetrično dimetilovanih arginina (ćelije tretirane referentnim jedinjenjem pri 10 µM). [0947] In the preceding equations, the following controls were used for normalization: Low control: minimum level of symmetrically dimethylated arginines (cells treated with reference compound at 10 µM).

[0948] Visoka kontrola: maksimalni nivo simetrično dimetilovanih arginina (ćelije tretirane pomoću DMSO). [0948] High control: maximal level of symmetrically dimethylated arginines (cells treated with DMSO).

[0949] Vrednosti IC50i pIC50(-logIC50) izračunate su koristeći odgovarajući softver. [0949] IC50 and pIC50(-logIC50) values were calculated using appropriate software.

[0950] Vrednosti pIC50u sledećoj tabeli su uprosečene vrednosti (Jed. br. označava jedinjenje broj; n.d. znači nije određeno). [0950] The pIC50 values in the following table are average values (Unit no. indicates compound number; n.d. means not determined).

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Primeri kompozicije Composition examples

[0951] „Aktivni sastojak“ (active ingredient, a.i.), kako se koristi u ovim primerima, odnosi se na jedinjenja formule (I) i njihove farmaceutski prihvatljive adicione soli i solvate; naročito na bilo koje od jedinjenja iz primera. [0951] "Active ingredient" (a.i.), as used in these examples, refers to compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates; especially to any of the compounds from the examples.

[0952] Uobičajeni primeri recepta za formulacije iz pronalaska su sledeći: [0952] Common examples of recipes for formulations of the invention are as follows:

1. Tablete 1. Tablets

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2. Suspenzija 2. Suspension

[0953] Vodena suspenzija se priprema za oralnu primenu tako da svaki mililitar sadrži 1 do 5 mg aktivnog sastojka, 50 mg natrijum karboksimetil celuloze, 1 mg natrijum benzoata, 500 mg sorbitola i vodu do 1 ml. [0953] The aqueous suspension is prepared for oral administration so that each milliliter contains 1 to 5 mg of the active ingredient, 50 mg of sodium carboxymethyl cellulose, 1 mg of sodium benzoate, 500 mg of sorbitol and water to 1 ml.

3. Injektabilna 3. Injectable

[0954] Parenteralna kompozicija se priprema mešanjem 1,5% (težina/zapremina) aktivnog sastojka u 0,9% rastvoru NaCl ili u 10% po zapremini propilen glikolu u vodi. [0954] The parenteral composition is prepared by mixing 1.5% (w/v) of the active ingredient in a 0.9% NaCl solution or in 10% by volume propylene glycol in water.

4. Mast 4. Grease

[0955] U ovom primeru, aktivni sastojak može da se zameni istom količinom bilo kog od jedinjenja iz predmetnog pronalaska, naročito istom količinom bilo kog od jedinjenja iz primera [0955] In this example, the active ingredient can be replaced by the same amount of any of the compounds from the present invention, especially by the same amount of any of the compounds from the examples

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Claims (34)

Patentni zahtevi 1. Jedinjenje formule (I) Patent claims 1. Compound of formula (I) pri čemu R<1>predstavlja vodonik ili -C(=O)-C1-4alkil; R<2>predstavlja vodonik ili -C(=O)-C1-4alkil; Y predstavlja -CH2- ili -CF2-; Z predstavlja -CH2-, -X-CR<5a>R<5b>-, -CR<5c>=CR<5d>-, -CR<5e>R<5g>-CR<5f>R<5h>-, -C≡C-, -O-, ili -CR<5a>R<5b>-X-; R<5a>, R<5b>, R<5c>, R<5d>, R<5e>, R<5f>, R<5g>i R<5h>svaki nezavisno predstavlja vodonik ili C1-4alkil; X predstavlja -O-, -S-, ili -NR<11>-; R<11>predstavlja vodonik, C1-4alkil, ili C1-4alkil supstituisan jednim supstituentom izabranim iz grupe koju čine -OH, -O-C1-4alkil, R<12>, -NH2, -NH-C1-4alkil i -N(C1-4alkil)2; R<12>predstavlja 4-, 5-, 6- ili 7-člani heterociklični prsten koji sadrži jedan atom azota i opciono jedan atom kiseonika, pri čemu je navedeni 4-, 5-, 6- ili 7-člani heterociklični prsten povezan sa ostatkom molekula preko atoma azota prstena; Ar predstavlja 10-člani biciklični aromatični sistem prstenova koji se sastoji od dva kondenzovana 6-člana prstena, whereby R<1> represents hydrogen or -C(=O)-C1-4alkyl; R<2> represents hydrogen or -C(=O)-C1-4alkyl; Y represents -CH2- or -CF2-; Z represents -CH2-, -X-CR<5a>R<5b>-, -CR<5c>=CR<5d>-, -CR<5e>R<5g>-CR<5f>R<5h>-, -C≡C-, -O-, or -CR<5a>R<5b>-X-; R<5a>, R<5b>, R<5c>, R<5d>, R<5e>, R<5f>, R<5g> and R<5h> each independently represents hydrogen or C1-4 alkyl; X represents -O-, -S-, or -NR<11>-; R<11> represents hydrogen, C1-4alkyl, or C1-4alkyl substituted with one substituent selected from the group consisting of -OH, -O-C1-4alkyl, R<12>, -NH2, -NH-C1-4alkyl and -N(C1-4alkyl)2; R<12>represents a 4-, 5-, 6- or 7-membered heterocyclic ring containing one nitrogen atom and optionally one oxygen atom, wherein said 4-, 5-, 6- or 7-membered heterocyclic ring is connected to the rest of the molecule via a nitrogen atom of the ring; Ar represents a 10-membered bicyclic aromatic ring system consisting of two fused 6-membered rings, pri čemu je najmanje 1 atom ugljenika prstena B zamenjen atomom azota; pri čemu je opciono 1 dodatni atom ugljenika prstena A ili prstena B zamenjen atomom azota, pod uslovom da, kada atom azota zamenjuje jedan od dva kondenzovana atoma ugljenika, karbonilna grupa je prisutna u navedenom bicikličnom aromatičnom sistemu prstenova; Ar je opciono supstituisan sa jednim, dva, tri ili četiri supstituenta od kojih je svaki nezavisno izabran iz grupe koju čine halo, -OH, -NH2, -NH-C1-4alkil, -N(C1-4alkil)2, -NHR<10d>, -NR<10c>R<10d>, cijano, -CF3, -C(=O)-NH2, -C(=O)-NH-C1-4alkil, -C(=O)-C1-4alkil, 4 C1-4alkiloksi, -C(=O)-O-C1-4alkil, C3-6cikloalkil, -O-C3-6cikloalkil, -NH-C3-6cikloalkil, -N(C3-6cikloalkil)2, C2-6alkenil, C1-4alkil supstituisan jednim C1-4alkiloksi i C1-4alkil opciono supstituisan jednim -NR<10a>R<10b>; R<10a>i R<10b>svaki nezavisno predstavlja vodonik ili C1-4alkil; R<10c>i R<10d>svaki nezavisno predstavlja C3-6cikloalkil; R<13>; R<14>; C3-6cikloalkil supstituisan sa jednim, dva ili tri supstituenta od kojih je svaki nezavisno izabran iz grupe koju čine halo, -OH i -O-C1-4alkil; C1-4alkil supstituisan sa jednim, dva ili tri supstituenta od kojih je svaki nezavisno izabran iz grupe koju čine halo, -OH i -O-C1- 4alkil; ili C1-4alkil supstituisan jednim supstituentom izabranim iz grupe koju čine C3- 6cikloalkil, R<13>i R<14>; R<13>predstavlja 4- do 7-člani monociklični aromatični prsten koji sadrži jedan, dva ili tri heteroatoma, svaki nezavisno izabran od O, S, S(=O)pi N; ili 6- do 11-člani biciklični kondenzovani aromatični prsten koji sadrži jedan, dva ili tri heteroatoma, svaki nezavisno izabran od O, S, S(=O)pi N; navedeni 4- do 7-člani monociklični aromatični prsten ili 6- do 11-člani biciklični kondenzovani aromatični prsten je opciono supstituisan sa jednim ili dva supstituenta izabrana iz grupe koju čini C1-4alkil; p predstavlja 1 ili 2; R<14>predstavlja fenil opciono supstituisan sa jednim, dva ili tri supstituenta od kojih je svaki nezavisno izabran iz grupe koju čini halo; Het predstavlja biciklični aromatični heterociklični sistem prstenova izabran iz grupe koju čine (a-1), (a-2), (a-3), (a-4) i (a-5): wherein at least 1 carbon atom of ring B is replaced by a nitrogen atom; wherein optionally 1 additional carbon atom of ring A or ring B is replaced by a nitrogen atom, provided that, when the nitrogen atom replaces one of the two fused carbon atoms, a carbonyl group is present in said bicyclic aromatic ring system; Ar is optionally substituted with one, two, three or four substituents each independently selected from the group consisting of halo, -OH, -NH2, -NH-C1-4alkyl, -N(C1-4alkyl)2, -NHR<10d>, -NR<10c>R<10d>, cyano, -CF3, -C(=O)-NH2, -C(=O)-NH-C1-4alkyl, -C(=O)-C1-4alkyl, 4 C1-4alkyloxy, -C(=O)-O-C1-4alkyl, C3-6cycloalkyl, -O-C3-6cycloalkyl, -NH-C3-6cycloalkyl, -N(C3-6cycloalkyl)2, C2-6alkenyl, C1-4alkyl substituted with one C1-4alkyloxy and C1-4alkyl optionally substituted with one -NR<10a>R<10b>; R<10a> and R<10b> each independently represents hydrogen or C1-4alkyl; R<10c> and R<10d> each independently represents C3-6cycloalkyl; R<13>; R<14>; C3-6cycloalkyl substituted with one, two or three substituents each independently selected from the group consisting of halo, -OH and -O-C1-4alkyl; C1-4alkyl substituted with one, two or three substituents each independently selected from the group consisting of halo, -OH and -O-C1- 4alkyl; or C1-4alkyl substituted with one substituent selected from the group consisting of C3- 6cycloalkyl, R<13> and R<14>; R<13>represents a 4- to 7-membered monocyclic aromatic ring containing one, two or three heteroatoms, each independently selected from O, S, S(=O) and N; or a 6- to 11-membered bicyclic fused aromatic ring containing one, two or three heteroatoms, each independently selected from O, S, S(=O) and N; said 4- to 7-membered monocyclic aromatic ring or 6- to 11-membered bicyclic fused aromatic ring is optionally substituted with one or two substituents selected from the group consisting of C1-4alkyl; p represents 1 or 2; R<14>represents phenyl optionally substituted with one, two or three substituents each independently selected from the group consisting of halo; Het represents a bicyclic aromatic heterocyclic ring system selected from the group consisting of (a-1), (a-2), (a-3), (a-4) and (a-5): R<3a>, R<3b>, R<3c>, R<3d>i R<3e>svaki nezavisno predstavlja vodonik, halo, -NR<7a>R<7b>, C1-4alkil, C2-4alkenil, C3-6cikloalkil, -OH ili -O-C1-4alkil; R<7a>predstavlja vodonik; R<7b>predstavlja vodonik, C3-6cikloalkil, ili C1-4alkil; 4 R<4a>, R<4b>, R<4c>, R<4d>, R<4e>, R<4f>i R<4g>svaki nezavisno predstavlja vodonik, halo, -NR<8a>R<8b>, ili C1-4alkil; R<8a>i R<8b>svaki nezavisno predstavlja vodonik ili C1-4alkil; Q<1>predstavlja N ili CR<6a>; Q<2>predstavlja N ili CR<6b>; Q<3>predstavlja N ili CR<6c>; Q<4>predstavlja N ili CR<6d>; pod uslovom da najviše jedan od Q<3>i Q<4>predstavlja N; Q<8>predstavlja N ili CR<6g>; Q<9>predstavlja N ili CR<6h>; Q<10>predstavlja N ili CR<6i>; Q<11>predstavlja N ili CR<6j>; Q<5>predstavlja CR<3d>; Q<6>predstavlja N; i Q<7>predstavlja CR<4f>; ili Q<5>predstavlja CR<3d>; Q<6>predstavlja CR<4e>; i Q<7>predstavlja N; ili Q<5>predstavlja N; Q<6>predstavlja CR<4e>; i Q<7>predstavlja CR<4f>; ili Q<5>predstavlja N; Q<6>predstavlja CR<4e>; i Q<7>predstavlja N; ili Q<5>predstavlja N; Q<6>predstavlja N; i Q<7>predstavlja CR<4f>; ili Q<5>predstavlja N; Q<6>predstavlja N; i Q<7>predstavlja N; R<6a>, R<6b>, R<6c>, R<6d>, R<6e>, R<6f>, R<6g>, R<6h>, R<6i>i R<6j>svaki nezavisno predstavlja vodonik, halogen, C1-4alkil, -NR<9a>R<9b>, ili C1-4alkil supstituisan sa jednim, dva ili tri halo atoma; R<9a>i R<9b>svaki nezavisno predstavlja vodonik ili C1-4alkil; ili njegova farmaceutski prihvatljiva adiciona so ili solvat. R<3a>, R<3b>, R<3c>, R<3d>and R<3e> each independently represents hydrogen, halo, -NR<7a>R<7b>, C1-4alkyl, C2-4alkenyl, C3-6cycloalkyl, -OH or -O-C1-4alkyl; R<7a>represents hydrogen; R<7b>represents hydrogen, C3-6cycloalkyl, or C1-4alkyl; 4 R<4a>, R<4b>, R<4c>, R<4d>, R<4e>, R<4f> and R<4g> each independently represents hydrogen, halo, -NR<8a>R<8b>, or C1-4alkyl; R<8a> and R<8b> each independently represents hydrogen or C1-4alkyl; Q<1>represents N or CR<6a>; Q<2>represents N or CR<6b>; Q<3>represents N or CR<6c>; Q<4>represents N or CR<6d>; provided that at most one of Q<3> and Q<4> represents N; Q<8> represents N or CR<6g>; Q<9> represents N or CR<6h>; Q<10>represents N or CR<6i>; Q<11> represents N or CR<6j>; Q<5> represents CR<3d>; Q<6>represents N; and Q<7>represents CR<4f>; or Q<5> represents CR<3d>; Q<6>represents CR<4e>; and Q<7>represents N; or Q<5>represents N; Q<6>represents CR<4e>; and Q<7>represents CR<4f>; or Q<5>represents N; Q<6>represents CR<4e>; and Q<7>represents N; or Q<5>represents N; Q<6>represents N; and Q<7>represents CR<4f>; or Q<5>represents N; Q<6>represents N; and Q<7>represents N; R<6a>, R<6b>, R<6c>, R<6d>, R<6e>, R<6f>, R<6g>, R<6h>, R<6i> and R<6j> each independently represents hydrogen, halogen, C1-4alkyl, -NR<9a>R<9b>, or C1-4alkyl substituted with one, two or three halo atoms; R<9a> and R<9b> each independently represents hydrogen or C1-4alkyl; or a pharmaceutically acceptable addition salt or solvate thereof. 2. Jedinjenje prema zahtevu 1, pri čemu Ar je opciono supstituisan sa jednim, dva, tri ili četiri supstituenta od kojih je svaki nezavisno izabran iz grupe koju čine halo, -OH, -NH2, -NH-C1-4alkil, -N(C1-4alkil)2, -NHR<10d>, -NR<10c>R<10d>, cijano, -CF3, -C(=O)-NH2, -C(=O)-NH-C1-4alkil, -C(=O)-C1-4alkil, C1-4alkiloksi, -C(=O)-O-C1-4alkil, C3-6cikloalkil, C2-6alkenil, C1-4alkil supstituisan jednim C1-4alkiloksi i C1-4alkil opciono supstituisan jednim - NR<10a>R<10b>; R<10c>i R<10d>svaki nezavisno predstavlja C3-6cikloalkil; C3-6cikloalkil supstituisan sa jednim, dva ili tri supstituenta od kojih je svaki nezavisno izabran iz grupe koju čine halo, -OH i -O-C1-4alkil; C1-4alkil supstituisan sa jednim, dva ili tri supstituenta od kojih je svaki nezavisno izabran iz grupe koju čine halo, -OH i -O-C1-4alkil; ili C1-4alkil supstituisan jednim supstituentom izabranim iz grupe koju čine C3-6cikloalkil, R<13>i R<14>; 4 Het predstavlja biciklični aromatični heterociklični sistem prstenova izabran iz grupe koju čine (a-1), (a-2) i (a-3): 2. A compound according to claim 1, wherein Ar is optionally substituted with one, two, three or four substituents each independently selected from the group consisting of halo, -OH, -NH2, -NH-C1-4alkyl, -N(C1-4alkyl)2, -NHR<10d>, -NR<10c>R<10d>, cyano, -CF3, -C(=O)-NH2, -C(=O)-NH-C1-4alkyl, -C(=O)-C1-4alkyl, C1-4alkyloxy, -C(=O)-O-C1-4alkyl, C3-6cycloalkyl, C2-6alkenyl, C1-4alkyl substituted with one C1-4alkyloxy and C1-4alkyl optionally substituted with one - NR<10a>R<10b>; R<10c> and R<10d> each independently represents C3-6cycloalkyl; C3-6cycloalkyl substituted with one, two or three substituents each independently selected from the group consisting of halo, -OH and -O-C1-4alkyl; C1-4alkyl substituted with one, two or three substituents each independently selected from the group consisting of halo, -OH and -O-C1-4alkyl; or C1-4alkyl substituted with one substituent selected from the group consisting of C3-6cycloalkyl, R<13> and R<14>; 4 Het represents a bicyclic aromatic heterocyclic ring system selected from the group consisting of (a-1), (a-2) and (a-3): R<3a>, R<3b>i R<3c>svaki nezavisno predstavlja vodonik, halo, -NR<7a>R<7b>, C1-4alkil ili -O-C1- 4alkil; R<7b>predstavlja vodonik ili C1-4alkil; R<4a>, R<4b>i R<4c>svaki nezavisno predstavlja vodonik, halo, -NR<8a>R<8b>, ili C1-4alkil; Q<1>predstavlja N ili CR<6a>; Q<2>predstavlja N ili CR<6b>; Q<3>predstavlja N ili CR<6c>; Q<4>predstavlja N ili CR<6d>; pod uslovom da najviše jedan od Q<3>i Q<4>predstavlja N; R<6a>, R<6b>, R<6c>, R<6d>, R<6e>i R<6f>svaki nezavisno predstavlja vodonik, halogen, C1-4alkil, -NR<9a>R<9b>, ili C1-4alkil supstituisan sa jednim, dva ili tri halo atoma. R<3a>, R<3b>and R<3c> each independently represents hydrogen, halo, -NR<7a>R<7b>, C1-4alkyl or -O-C1- 4alkyl; R<7b>represents hydrogen or C1-4alkyl; R<4a>, R<4b> and R<4c> each independently represents hydrogen, halo, -NR<8a>R<8b>, or C1-4alkyl; Q<1>represents N or CR<6a>; Q<2>represents N or CR<6b>; Q<3>represents N or CR<6c>; Q<4>represents N or CR<6d>; provided that at most one of Q<3> and Q<4> represents N; R<6a>, R<6b>, R<6c>, R<6d>, R<6e> and R<6f> each independently represents hydrogen, halogen, C1-4alkyl, -NR<9a>R<9b>, or C1-4alkyl substituted with one, two or three halo atoms. 3. Jedinjenje prema zahtevu 1 ili 2, pri čemu Ar je opciono supstituisan sa jednim, dva, tri ili četiri supstituenta od kojih je svaki nezavisno izabran iz grupe koju čine halo, -OH, -NH2, -NH-C1-4alkil, -N(C1-4alkil)2, cijano, -CF3, -C(=O)-NH-C1-4alkil, -C(=O)-C1-4alkil, C1-4alkiloksi i C1-4alkil opciono supstituisan jednim -NR<10a>R<10b>; Het predstavlja biciklični aromatični heterociklični sistem prstenova izabran iz grupe koju čine (a-1), (a-2) i (a-3): 3. A compound according to claim 1 or 2, wherein Ar is optionally substituted with one, two, three or four substituents each independently selected from the group consisting of halo, -OH, -NH2, -NH-C1-4alkyl, -N(C1-4alkyl)2, cyano, -CF3, -C(=O)-NH-C1-4alkyl, -C(=O)-C1-4alkyl, C1-4alkyloxy and C1-4alkyl optionally substituted with one -NR<10a>R<10b>; Het represents a bicyclic aromatic heterocyclic ring system selected from the group consisting of (a-1), (a-2) and (a-3): R<3a>, R<3b>i R<3c>svaki nezavisno predstavlja vodonik, halo, -NR<7a>R<7b>, ili -O-C1-4alkil; R<7b>predstavlja vodonik ili C1-4alkil; R<4a>, R<4b>i R<4c>svaki nezavisno predstavlja vodonik, halo, -NR<8a>R<8b>, ili C1-4alkil; Q<1>predstavlja N ili CR<6a>; Q<2>predstavlja N ili CR<6b>; Q<3>predstavlja N ili CR<6c>; Q<4>predstavlja N ili CR<6d>; pod uslovom da najviše jedan od Q<3>i Q<4>predstavlja N; R<6a>, R<6b>, R<6c>, R<6d>, R<6e>i R<6f>svaki nezavisno predstavlja vodonik, halogen, C1-4alkil, -NR<9a>R<9b>, ili C1-4alkil supstituisan sa jednim, dva ili tri halo atoma. R<3a>, R<3b> and R<3c> each independently represents hydrogen, halo, -NR<7a>R<7b>, or -O-C1-4alkyl; R<7b>represents hydrogen or C1-4alkyl; R<4a>, R<4b> and R<4c> each independently represents hydrogen, halo, -NR<8a>R<8b>, or C1-4alkyl; Q<1>represents N or CR<6a>; Q<2>represents N or CR<6b>; Q<3>represents N or CR<6c>; Q<4>represents N or CR<6d>; provided that at most one of Q<3> and Q<4> represents N; R<6a>, R<6b>, R<6c>, R<6d>, R<6e> and R<6f> each independently represents hydrogen, halogen, C1-4alkyl, -NR<9a>R<9b>, or C1-4alkyl substituted with one, two or three halo atoms. 4. Jedinjenje prema zahtevu 1, pri čemu R<1>predstavlja vodonik; R<2>predstavlja vodonik; Y predstavlja -CH2-; Z predstavlja -X-CR<5a>R<5b>-, -CR<5e>R<5g>-CR<5f>R<5h>-, ili -CR<5a>R<5b>-X-; R<5a>, R<5b>, R<5e>, R<5f>, R<5g>i R<5h>predstavljaju vodonik; X predstavlja -O-; Ar predstavlja 4. A compound according to claim 1, wherein R<1>represents hydrogen; R<2>represents hydrogen; Y represents -CH2-; Z represents -X-CR<5a>R<5b>-, -CR<5e>R<5g>-CR<5f>R<5h>-, or -CR<5a>R<5b>-X-; R<5a>, R<5b>, R<5e>, R<5f>, R<5g> and R<5h> represent hydrogen; X represents -O-; Ar represents pri čemu je Ar opciono supstituisan na poziciji označenoj sa α, supstituentom izabranim iz grupe koju čine -NH2, -NH-C1-4alkil i -NHR<10d>; i pri čemu je Ar opciono supstituisan na poziciji označenoj sa β, supstituentom izabranim iz grupe koju čine halo i CF3; pod uslovom da je Ar supstituisan na najmanje jednoj od pozicija označenih sa α ili β; 4 1 R<10d>predstavlja C3-6cikloalkil; C1-4alkil supstituisan sa jednim, dva ili tri halo supstituenta; ili C1-4alkil supstituisan jednim C3-6cikloalkil supstituentom; Het predstavlja biciklični aromatični heterociklični sistem prstenova izabran iz grupe koju čine (a-1) i (a-4); R<3a>i R<3d>svaki nezavisno predstavlja vodonik, halo, -NR<7a>R<7b>, C1-4alkil, ili -O-C1-4alkil; R<7a>predstavlja vodonik; R<7b>predstavlja vodonik ili C1-4alkil; R<4a>, R<4d>i R<4f>svaki nezavisno predstavlja vodonik ili halo; Q<1>predstavlja CR<6a>; Q<2>predstavlja CR<6b>; Q<8>predstavlja CR<6g>; Q<9>predstavlja CR<6h>; Q<5>predstavlja CR<3d>; Q<6>predstavlja N; i Q<7>predstavlja CR<4f>; R<6a>, R<6b>, R<6g>, i R<6h>predstavljaju vodonik. wherein Ar is optionally substituted at the position indicated by α, with a substituent selected from the group consisting of -NH2, -NH-C1-4alkyl and -NHR<10d>; and wherein Ar is optionally substituted at the position indicated by β with a substituent selected from the group consisting of halo and CF 3 ; provided that Ar is substituted in at least one of the positions indicated by α or β; 4 1 R<10d> represents C3-6cycloalkyl; C 1-4 alkyl substituted with one, two or three halo substituents; or C1-4alkyl substituted with one C3-6cycloalkyl substituent; Het represents a bicyclic aromatic heterocyclic ring system selected from the group consisting of (a-1) and (a-4); R<3a> and R<3d> each independently represents hydrogen, halo, -NR<7a>R<7b>, C1-4alkyl, or -O-C1-4alkyl; R<7a>represents hydrogen; R<7b>represents hydrogen or C1-4alkyl; R<4a>, R<4d> and R<4f> each independently represents hydrogen or halo; Q<1> represents CR<6a>; Q<2> represents CR<6b>; Q<8> represents CR<6g>; Q<9> represents CR<6h>; Q<5> represents CR<3d>; Q<6>represents N; and Q<7>represents CR<4f>; R<6a>, R<6b>, R<6g>, and R<6h> represent hydrogen. 5. Jedinjenje prema bilo kom od zahteva 1 do 4, pri čemu R<1>predstavlja vodonik; R<2>predstavlja vodonik; Y predstavlja -CH2-; Z predstavlja -X-CR<5a>R<5b>- ili -CR<5e>R<5g>-CR<5f>R<5h>-; R<5a>, R<5b>, R<5e>, R<5f>, R<5g>i R<5h>predstavljaju vodonik; X predstavlja -O-; Ar predstavlja 5. A compound according to any one of claims 1 to 4, wherein R<1>represents hydrogen; R<2>represents hydrogen; Y represents -CH2-; Z represents -X-CR<5a>R<5b>- or -CR<5e>R<5g>-CR<5f>R<5h>-; R<5a>, R<5b>, R<5e>, R<5f>, R<5g> and R<5h> represent hydrogen; X represents -O-; Ar represents pri čemu je Ar opciono supstituisan na poziciji označenoj sa α, supstituentom izabranim iz grupe koju čine -NH2, -NH-C1-4alkil i -NHR<10d>; i pri čemu je Ar opciono supstituisan na poziciji označenoj sa β, supstituentom izabranim iz grupe koju čine halo i CF3; pod uslovom da je Ar supstituisan na najmanje jednoj od pozicija označenih sa α ili β; R<10d>predstavlja C3-6cikloalkil; C1-4alkil supstituisan sa jednim, dva ili tri halo supstituenta; ili C1-4alkil supstituisan jednim C3-6cikloalkil supstituentom; Het predstavlja biciklični aromatični heterociklični sistem prstenova izabran iz grupe koju čini (a-1); 4 2 R<3a>predstavlja vodonik, halo, -NR<7a>R<7b>, C1-4alkil, ili -O-C1-4alkil; R<7a>predstavlja vodonik; R<7b>predstavlja vodonik ili C1-4alkil; R<4a>predstavlja vodonik ili halo; Q<1>predstavlja CR<6a>; Q<2>predstavlja CR<6b>; R<6a>i R<6b>predstavljaju vodonik. wherein Ar is optionally substituted at the position indicated by α, with a substituent selected from the group consisting of -NH2, -NH-C1-4alkyl and -NHR<10d>; and wherein Ar is optionally substituted at the position indicated by β with a substituent selected from the group consisting of halo and CF 3 ; provided that Ar is substituted in at least one of the positions indicated by α or β; R<10d> represents C3-6cycloalkyl; C 1-4 alkyl substituted with one, two or three halo substituents; or C1-4alkyl substituted with one C3-6cycloalkyl substituent; Het represents a bicyclic aromatic heterocyclic ring system selected from the group consisting of (a-1); 4 2 R<3a>represents hydrogen, halo, -NR<7a>R<7b>, C1-4alkyl, or -O-C1-4alkyl; R<7a>represents hydrogen; R<7b>represents hydrogen or C1-4alkyl; R<4a>represents hydrogen or halo; Q<1> represents CR<6a>; Q<2> represents CR<6b>; R<6a>and R<6b>represent hydrogen. 6. Jedinjenje prema zahtevu 1 ili 2, pri čemu R<1>predstavlja vodonik; R<2>predstavlja vodonik; Y predstavlja -CH2-; Z predstavlja -CR<5e>R<5g>-CR<5f>R<5h>-; R<5e>, R<5f>, R<5g>i R<5h>predstavljaju vodonik; Ar predstavlja bilo koji od sledećih 10-članih bicikličnih aromatičnih sistema prstenova: 6. A compound according to claim 1 or 2, wherein R<1>represents hydrogen; R<2>represents hydrogen; Y represents -CH2-; Z represents -CR<5e>R<5g>-CR<5f>R<5h>-; R<5e>, R<5f>, R<5g> and R<5h> represent hydrogen; Ar represents any of the following 10-membered bicyclic aromatic ring systems: Ar je opciono supstituisan sa jednim, dva, tri ili četiri supstituenta od kojih je svaki nezavisno izabran iz grupe koju čine halo, -NH2, -NH-C1-4alkil, -N(C1-4alkil)2, - NHR<10d>, -NR<10c>R<10d>; R<10c>i R<10d>svaki nezavisno predstavlja C3-6cikloalkil; C3-6cikloalkil supstituisan sa jednim, dva ili tri supstituenta od kojih je svaki nezavisno izabran iz grupe koju čine halo, -OH i -O-C1-4alkil; C1-4alkil supstituisan sa jednim, dva ili tri supstituenta od kojih je svaki nezavisno izabran iz grupe koju čine halo, -OH i - O-C1-4alkil; ili C1-4alkil supstituisan jednim C3-6cikloalkil supstituentom; Het predstavlja biciklični aromatični heterociklični sistem prstenova izabran iz grupe koju čini (a-1); R<3a>predstavlja vodonik, -NR<7a>R<7b>, ili -O-C1-4alkil; R<7a>predstavlja vodonik; R<7b>predstavlja vodonik ili C1-4alkil; R<4a>predstavlja vodonik; 4 Q<1>predstavlja CR<6a>; Q<2>predstavlja CR<6b>; R<6a>i R<6b>predstavljaju vodonik. Ar is optionally substituted with one, two, three or four substituents each independently selected from the group consisting of halo, -NH2, -NH-C1-4alkyl, -N(C1-4alkyl)2, -NHR<10d>, -NR<10c>R<10d>; R<10c> and R<10d> each independently represents C3-6cycloalkyl; C3-6cycloalkyl substituted with one, two or three substituents each independently selected from the group consisting of halo, -OH and -O-C1-4alkyl; C1-4alkyl substituted with one, two or three substituents each independently selected from the group consisting of halo, -OH and -O-C1-4alkyl; or C1-4alkyl substituted with one C3-6cycloalkyl substituent; Het represents a bicyclic aromatic heterocyclic ring system selected from the group consisting of (a-1); R<3a> represents hydrogen, -NR<7a>R<7b>, or -O-C1-4alkyl; R<7a>represents hydrogen; R<7b>represents hydrogen or C1-4alkyl; R<4a>represents hydrogen; 4 Q<1> represents CR<6a>; Q<2> represents CR<6b>; R<6a>and R<6b>represent hydrogen. 7. Jedinjenje prema zahtevu 1, 2 ili 6, pri čemu Ar je izabran iz grupe koju čine: 7. A compound according to claim 1, 2 or 6, wherein Ar was selected from a group consisting of: pri čemu je svaki Ar opciono supstituisan na poziciji α, supstituentom izabranim iz grupe koju čine -NH2, -NH-C1-4alkil, -N(C1-4alkil)2, -NHR<10d>i -NR<10c>R<10d>; i pri čemu je Ar opciono supstituisan na drugoj poziciji halo supstituentom. wherein each Ar is optionally substituted in position α, with a substituent selected from the group consisting of -NH2, -NH-C1-4alkyl, -N(C1-4alkyl)2, -NHR<10d> and -NR<10c>R<10d>; and wherein Ar is optionally substituted at the second position with a halo substituent. 8. Jedinjenje prema zahtevu 1, pri čemu Y predstavlja -CH2-; Z predstavlja -X-CR<5a>R<5b>- ili -CH2CH2-; R<5a>i R<5b>predstavljaju vodonik; X predstavlja -O-; R<11>predstavlja vodonik; Ar predstavlja 8. The compound according to claim 1, wherein Y represents -CH2-; Z represents -X-CR<5a>R<5b>- or -CH2CH2-; R<5a> and R<5b> represent hydrogen; X represents -O-; R<11>represents hydrogen; Ar represents Ar je opciono supstituisan sa jednim ili dva supstituenta od kojih je svaki nezavisno izabran iz grupe koju čine halo, -OH, -NH2, -NH-C1-4alkil, -N(C1-4alkil)2, cijano i -CF3; Het predstavlja biciklični aromatični heterociklični sistem prstenova izabran iz grupe koju čini (a-1); R<3a>predstavlja -NR<7a>R<7b>; R<7a>predstavlja vodonik; R<7b>predstavlja vodonik; R<4a>predstavlja vodonik; Q<1>predstavlja CR<6a>; Q<2>predstavlja CR<6b>; R<6a>i R<6b>predstavljaju vodonik. Ar is optionally substituted with one or two substituents each independently selected from the group consisting of halo, -OH, -NH2, -NH-C1-4alkyl, -N(C1-4alkyl)2, cyano and -CF3; Het represents a bicyclic aromatic heterocyclic ring system selected from the group consisting of (a-1); R<3a>represents -NR<7a>R<7b>; R<7a>represents hydrogen; R<7b>represents hydrogen; R<4a>represents hydrogen; Q<1> represents CR<6a>; Q<2> represents CR<6b>; R<6a>and R<6b>represent hydrogen. 9. Jedinjenje prema zahtevu 1, 2, 3 ili 6, pri čemu Ar predstavlja 9. A compound according to claim 1, 2, 3 or 6, wherein Ar represents 4 4 4 4 10. Jedinjenje prema zahtevu 1, 2, 3, 7, 8 ili 9, pri čemu R<1>i R<2>predstavljaju vodonik. 10. A compound according to claim 1, 2, 3, 7, 8 or 9, wherein R<1> and R<2> represent hydrogen. 11. Jedinjenje prema bilo kom od zahteva 1 do 3, zahtevu 7 i zahtevima 9 do 10, pri čemu Y predstavlja -CH2-. 11. A compound according to any one of claims 1 to 3, claim 7 and claims 9 to 10, wherein Y represents -CH2-. 12. Jedinjenje prema zahtevu 11, pri čemu Z predstavlja -CH2CH2-. 12. A compound according to claim 11, wherein Z represents -CH2CH2-. 13. Jedinjenje prema bilo kom od zahteva 1 do 4, zahtevu 7 i zahtevima 9 do 12, pri čemu Het predstavlja biciklični aromatični heterociklični sistem prstenova formule (a-1). 13. A compound according to any one of claims 1 to 4, claim 7 and claims 9 to 12, wherein Het represents a bicyclic aromatic heterocyclic ring system of formula (a-1). 14. Jedinjenje prema zahtevu 13, pri čemu R<3a>predstavlja -NR<7a>R<7b>; i R<7a>i R<7b>predstavljaju vodonik. 14. The compound according to claim 13, wherein R<3a>represents -NR<7a>R<7b>; and R<7a> and R<7b>represent hydrogen. 15. Jedinjenje prema bilo kom od zahteva 1 do 5, pri čemu R<5b>, R<5g>i R<5h>predstavljaju vodonik; Y predstavlja -CH2-; Het predstavlja (a-1); Q<1>predstavlja CH; i Q<2>predstavlja CH. 15. A compound according to any one of claims 1 to 5, wherein R<5b>, R<5g> and R<5h> represent hydrogen; Y represents -CH2-; Het represents (a-1); Q<1>represents CH; and Q<2>represents CH. 16. Jedinjenje prema zahtevu 1, pri čemu je jedinjenje 16. The compound according to claim 1, wherein the compound is ili njegova farmaceutski prihvatljiva adiciona so ili solvat. or a pharmaceutically acceptable addition salt or solvate thereof. 17. Jedinjenje prema zahtevu 16, pri čemu je jedinjenje 4 17. The compound according to claim 16, wherein the compound is 4 18. Farmaceutska kompozicija koja sadrži farmaceutski prihvatljivi nosač i, kao aktivni sastojak, terapeutski delotvornu količinu jedinjenja prema bilo kom od zahteva 1 do 17. 18. A pharmaceutical composition containing a pharmaceutically acceptable carrier and, as an active ingredient, a therapeutically effective amount of a compound according to any one of claims 1 to 17. 19. Jedinjenje prema definiciji iz bilo kog od zahteva 1 do 18 za upotrebu kao lek. 19. A compound as defined in any one of claims 1 to 18 for use as a medicine. 20. Jedinjenje prema definiciji iz bilo kog od zahteva 1 do 18 za upotrebu u lečenju ili prevenciji bolesti ili stanja izabranih od hematološkog poremećaja, metaboličkih poremećaja, autoimunskih poremećaja, kancera, inflamatornih bolesti, kardiovaskularnih bolesti, neurodegenerativnih bolesti, pankreatitisa, zatajenja više organa, bolesti bubrega, agregacije trombocita, pokretljivosti sperme, odbacivanja transplantata, odbacivanja grafta i povreda pluća. 20. A compound as defined in any one of claims 1 to 18 for use in the treatment or prevention of a disease or condition selected from a hematological disorder, metabolic disorder, autoimmune disorder, cancer, inflammatory disease, cardiovascular disease, neurodegenerative disease, pancreatitis, multiple organ failure, kidney disease, platelet aggregation, sperm motility, transplant rejection, graft rejection, and lung injury. 21. Jedinjenje za upotrebu prema zahtevu 20 za upotrebu u lečenju bolesti ili stanja izabranih od hematološkog poremećaja, metaboličkih poremećaja, autoimunskih poremećaja, kancera, inflamatornih bolesti, kardiovaskularnih bolesti, neurodegenerativnih bolesti, pankreatitisa, zatajenja više organa, bolesti bubrega, agregacije trombocita, pokretljivosti sperme, odbacivanja transplantata, odbacivanja grafta i povreda pluća. 21. A compound for use according to claim 20 for use in the treatment of a disease or condition selected from a hematological disorder, metabolic disorder, autoimmune disorder, cancer, inflammatory disease, cardiovascular disease, neurodegenerative disease, pancreatitis, multiple organ failure, kidney disease, platelet aggregation, sperm motility, graft rejection, graft rejection, and lung injury. 22. Jedinjenje za upotrebu iz zahteva 20 ili 21, pri čemu je bolest ili stanje autoimunski poremećaj, kancer, inflamatorna bolest ili neurodegenerativna bolest. 22. The compound for use of claim 20 or 21, wherein the disease or condition is an autoimmune disorder, cancer, inflammatory disease, or neurodegenerative disease. 23. Jedinjenje za upotrebu iz zahteva 22, pri čemu je bolest ili stanje kancer. 23. The compound for use of claim 22, wherein the disease or condition is cancer. 24. Jedinjenje za upotrebu iz zahteva 23, pri čemu je kancer non-Hodžkinov limfom. 24. The compound for use of claim 23, wherein the cancer is non-Hodgkin's lymphoma. 25. Jedinjenje za upotrebu iz zahteva 24, pri čemu je non-Hodžkinov limfom B-ćelijski non-Hodžkinov limfom. 4 25. The compound for use of claim 24, wherein the non-Hodgkin's lymphoma is B-cell non-Hodgkin's lymphoma. 4 26. Jedinjenje za upotrebu iz zahteva 23, pri čemu, kancer je kancer pluća. 26. The compound for use of claim 23, wherein the cancer is lung cancer. 27. Jedinjenje za upotrebu iz zahteva 26, pri čemu je kancer pluća nemikrocelularni kancer pluća ili mikrocelularni kancer pluća. 27. The compound for use of claim 26, wherein the lung cancer is non-small cell lung cancer or small cell lung cancer. 28. Jedinjenje za upotrebu iz zahteva 23, pri čemu, kancer je kancer hematopoetskog sistema. 28. The compound for use of claim 23, wherein the cancer is a cancer of the hematopoietic system. 29. Jedinjenje za upotrebu iz zahteva 28, pri čemu, kancer hematopoetskog sistema je leukemija. 29. The compound for use of claim 28, wherein the cancer of the hematopoietic system is leukemia. 30. Jedinjenje za upotrebu iz zahteva 29, pri čemu, leukemija je akutna mijelocitna leukemija, hronična limfocitna leukemija ili akutna limfocitna leukemija. 30. The compound for use of claim 29, wherein the leukemia is acute myelocytic leukemia, chronic lymphocytic leukemia, or acute lymphocytic leukemia. 31. Jedinjenje za upotrebu iz zahteva 23, pri čemu, kancer je melanom ili adenoidni cistični karcinom. 31. The compound for use of claim 23, wherein the cancer is melanoma or adenoid cystic carcinoma. 32. Jedinjenje za upotrebu iz zahteva 23, pri čemu, kancer je kancer pankreasa, kancer prostate, kancer debelog creva, kancer rektuma, holangiokarcinom, kancer glave i vrata, kancer nadbubrežne žlezde, kancer dojke, intraokularni melanom, kancer jajnika, mijelodisplastični sindromi (MDS) ili kancer pljuvačne žlezde. 32. The compound for use of claim 23, wherein the cancer is pancreatic cancer, prostate cancer, colon cancer, rectal cancer, cholangiocarcinoma, head and neck cancer, adrenal cancer, breast cancer, intraocular melanoma, ovarian cancer, myelodysplastic syndromes (MDS), or salivary gland cancer. 33. Jedinjenje za upotrebu iz zahteva 23, pri čemu, kancer je kancer pankreasa. 33. The compound for use of claim 23, wherein the cancer is pancreatic cancer. 34. Jedinjenje definisano u zahtevu 16 ili 17 za upotrebu u lečenju proliferativnog poremećaja. Izdaje i štampa: Zavod za intelektualnu svojinu, Beograd, Kneginje Ljubice 5 434. A compound as defined in claim 16 or 17 for use in the treatment of a proliferative disorder. Published and printed by: Institute for Intellectual Property, Belgrade, Kneginje Ljubice 5 4
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Families Citing this family (67)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
TWI730980B (en) 2015-08-26 2021-06-21 比利時商健生藥品公司 Novel 6-6 bicyclic aromatic ring substituted nucleoside analogues for use as prmt5 inhibitors
JP6909799B2 (en) * 2016-03-10 2021-07-28 ヤンセン ファーマシューティカ エヌ．ベー． Substituted nucleoside analogs for use as PRMT5 inhibitors
CA2969295A1 (en) * 2016-06-06 2017-12-06 Pfizer Inc. Substituted carbonucleoside derivatives, and use thereof as a prmt5 inhibitor
US12084462B2 (en) 2016-09-14 2024-09-10 Janssen Pharmaceutica Nv Spiro bicyclic inhibitors of menin-MLL interaction
SI3512857T1 (en) 2016-09-14 2021-07-30 Janssen Pharmaceutica Nv Spiro bicyclic inhibitors of menin-mll interaction
TWI753016B (en) 2016-09-14 2022-01-21 比利時商健生藥品公司 Fused bicyclic inhibitors of menin-mll interaction
AU2017338269B2 (en) 2016-10-03 2021-03-25 Janssen Pharmaceutica Nv Novel monocyclic and bicyclic ring system substituted carbanucleoside analogues for use as PRMT5 inhibitors
WO2018065365A1 (en) 2016-10-03 2018-04-12 Janssen Pharmaceutica Nv Novel monocyclic and bicyclic ring system substituted carbanucleoside analogues for use as prmt5 inhibitors
US10745409B2 (en) 2016-12-15 2020-08-18 Janssen Pharmaceutica Nv Azepane inhibitors of menin-MLL interaction
GB201700526D0 (en) * 2017-01-12 2017-03-01 Univ Of Hull Therapeutic use
WO2018154104A1 (en) 2017-02-27 2018-08-30 Janssen Pharmaceutica Nv Use of biomarkers in identifying cancer patients that will be responsive to treatment with a prmt5 inhibitor
EP3939986A1 (en) * 2017-08-09 2022-01-19 Prelude Therapeutics, Incorporated Selective inhibitors of protein arginine methyltransferase 5 (prmt5)
US11524962B2 (en) 2017-10-26 2022-12-13 Prelude Therapeutics, Incorporated Substituted pyrrolo[2,3-d]pyrimidines as inhibitors of protein arginine methyl transferase 5 (PRMT5)
JP2021505583A (en) * 2017-12-05 2021-02-18 エンジェクス ファーマシューティカル インコーポレイテッド Heterocyclic compounds as PMRT5 inhibitors
WO2020243178A1 (en) * 2019-05-30 2020-12-03 Angex Pharmaceutical, Inc. Heterocyclic compounds as prmt5 inhibitors
BR112020010815A2 (en) 2017-12-08 2020-11-10 Janssen Pharmaceutica Nv spirobicyclic analogs
CU24621B1 (en) * 2017-12-13 2022-09-08 Lupin Ltd SUBSTITUTED BICYCLIC HETEROCYCLIC COMPONENTS AS PRMT5 INHIBITORS
US11396517B1 (en) 2017-12-20 2022-07-26 Janssen Pharmaceutica Nv Exo-aza spiro inhibitors of menin-MLL interaction
JP7328241B2 (en) * 2018-03-14 2023-08-16 プレリュード セラピューティクス，インコーポレイティド Selective inhibitor of protein arginine methyltransferase 5 (PRMT5)
US10711007B2 (en) 2018-03-14 2020-07-14 Prelude Therapeutics Incorporated Selective inhibitors of protein arginine methyltransferase 5 (PRMT5)
EP3833669A4 (en) * 2018-08-07 2022-05-11 Merck Sharp & Dohme Corp. PRMT5 INHIBITORS
EP3833668B1 (en) * 2018-08-07 2025-03-19 Merck Sharp & Dohme LLC Prmt5 inhibitors
WO2020033284A1 (en) 2018-08-07 2020-02-13 Merck Sharp & Dohme Corp. Prmt5 inhibitors
US12173026B2 (en) 2018-08-07 2024-12-24 Merck Sharp & Dohme Llc PRMT5 inhibitors
EP3897667A4 (en) 2018-12-21 2023-04-19 Memorial Sloan Kettering Cancer Center SALICYL ADENOSIN MONOSULFAMATE ANALOGUES AND THEIR USES
CN109400545B (en) * 2018-12-24 2022-03-25 济南大学 Arginine methyltransferase 5 inhibitor and application thereof
CN109369507A (en) * 2018-12-26 2019-02-22 重庆市碚圣医药科技股份有限公司 A kind of method of purification of N- (2,2- diethoxy ethyl) phthalimide
KR20210129051A (en) * 2019-02-13 2021-10-27 프렐루드 테라퓨틱스, 인코포레이티드 Selective inhibitor of protein arginine methyltransferase 5 (PRMT5)
EP3939988A4 (en) * 2019-03-20 2022-08-24 Korea Research Institute of Chemical Technology PHARMACEUTICAL COMPOSITION COMPRISING A NEW HETEROCYCLIC COMPOUND AZOLOPYRIMIDINE AS ACTIVE SUBSTANCE
CA3134779A1 (en) * 2019-03-25 2020-10-01 California Institute Of Technology Prmt5 inhibitors and uses thereof
KR20210145787A (en) 2019-04-02 2021-12-02 알리고스 테라퓨틱스 인코포레이티드 Compounds targeting PRMT5
JP2022527556A (en) * 2019-04-05 2022-06-02 プレリュード・セラピューティクス・インコーポレイテッド Selective inhibitor of protein arginine methyltransferase 5
US12440506B2 (en) 2019-04-05 2025-10-14 Prelude Therapeutics, Incorporated Selective inhibitors of protein arginine methyltransferase 5 (PRMT5)
TW202112375A (en) 2019-06-06 2021-04-01 比利時商健生藥品公司 Methods of treating cancer using prmt5 inhibitors
PH12021553082A1 (en) * 2019-06-10 2023-09-11 Lupin Ltd Prmt5 inhibitors
KR20220019766A (en) * 2019-06-12 2022-02-17 얀센 파마슈티카 엔.브이. Novel spirobicyclic intermediate
EP4031555A1 (en) 2019-09-18 2022-07-27 Prelude Therapeutics, Incorporated Selective inhibitors of protein arginine methyltransferase 5 (prmt5)
WO2021079196A2 (en) * 2019-10-21 2021-04-29 Accent Therapeutics, Inc Mettl3 modulators
JP7624985B2 (en) * 2019-10-22 2025-01-31 ルピン・リミテッド Combination medicine of PRMT5 inhibitor
GB201915447D0 (en) * 2019-10-24 2019-12-11 Johnson Matthey Plc Polymorphs of avapritinib and methods of preparing the polymorphs
CN115135651A (en) * 2019-12-03 2022-09-30 鲁皮恩有限公司 Substituted nucleoside analogs as PRMT5 inhibitors
EP4076460A4 (en) 2019-12-17 2023-11-15 Merck Sharp & Dohme LLC Prmt5 inhibitors
IL293965A (en) 2019-12-19 2022-08-01 Janssen Pharmaceutica Nv Substituted straight chain spiro derivatives
AR121356A1 (en) 2020-02-18 2022-05-11 Gilead Sciences Inc ANTIVIRAL COMPOUNDS
TWI874791B (en) * 2020-02-18 2025-03-01 美商基利科學股份有限公司 Antiviral compounds
TWI883391B (en) 2020-02-18 2025-05-11 美商基利科學股份有限公司 Antiviral compounds
CN111233869B (en) * 2020-03-12 2022-09-16 杭州新博思生物医药有限公司 New compounds for preparing key intermediates of Remdesivir and preparation method thereof
WO2021202480A1 (en) * 2020-04-01 2021-10-07 Aligos Therapeutics, Inc. Compounds targeting prmt5
US20240101589A1 (en) * 2020-10-08 2024-03-28 Strom Therapeutics Limited Inhibitors of mettl3
CN112645875A (en) * 2020-12-09 2021-04-13 深圳海王医药科技研究院有限公司 Preparation method of procaterol hydrochloride impurity
EP4323362B1 (en) 2021-04-16 2025-05-07 Gilead Sciences, Inc. Methods of preparing carbanucleosides using amides
CN113234079B (en) * 2021-04-30 2022-02-01 上海湃隆生物科技有限公司 Nucleoside analogs as PRMT5 inhibitors
TW202321246A (en) * 2021-07-20 2023-06-01 大陸商上海齊魯製藥研究中心有限公司 PRMT5 inhibitor
CN115703796A (en) * 2021-08-09 2023-02-17 苏州恩泰新材料科技有限公司 Preparation method of important intermediate of Reidesciclovir
CA3228162A1 (en) 2021-08-18 2023-02-23 Gilead Sciences, Inc. Phospholipid compounds and methods of making and using the same
GB202117230D0 (en) 2021-11-29 2022-01-12 Argonaut Therapeutics Ltd Peptide vaccine
GB202203588D0 (en) 2022-03-15 2022-04-27 Argonaut Therapeutics Ltd Cancer diagnostic
CN116655638B (en) * 2022-05-12 2024-01-26 上海齐鲁制药研究中心有限公司 Deuterated PRMT5 inhibitors
CN116003339B (en) * 2022-12-01 2024-06-28 南京师范大学 Macrophage migration inhibition factor MIF two-photon fluorescent probe and preparation method and application thereof
WO2024170488A1 (en) 2023-02-13 2024-08-22 Astrazeneca Ab Prmt5 inhibitor for use in cancer therapy
WO2024229406A1 (en) 2023-05-04 2024-11-07 Revolution Medicines, Inc. Combination therapy for a ras related disease or disorder
WO2025034702A1 (en) 2023-08-07 2025-02-13 Revolution Medicines, Inc. Rmc-6291 for use in the treatment of ras protein-related disease or disorder
TW202530228A (en) 2023-10-12 2025-08-01 美商銳新醫藥公司 Ras inhibitors
EP4553080A1 (en) 2023-11-07 2025-05-14 Ustav Organicke Chemie a Biochemie AV CR, v.v.i. Nucleoside derivatives as antiviral agents against coronaviruses
WO2025171296A1 (en) 2024-02-09 2025-08-14 Revolution Medicines, Inc. Ras inhibitors
WO2025240847A1 (en) 2024-05-17 2025-11-20 Revolution Medicines, Inc. Ras inhibitors
WO2025255438A1 (en) 2024-06-07 2025-12-11 Revolution Medicines, Inc. Methods of treating a ras protein-related disease or disorder

Family Cites Families (38)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4224438A (en) 1970-07-14 1980-09-23 Boehringer Mannheim Gmbh Adenosine-5'-carboxylic acid amides
US6143749A (en) 1995-06-07 2000-11-07 Abbott Laboratories Heterocyclic substituted cyclopentane compounds
AU2002351077A1 (en) 2001-11-05 2003-05-19 Exiqon A/S Oligonucleotides modified with novel alpha-l-rna analogues
US7034147B2 (en) 2001-11-29 2006-04-25 Irm Llc Nucleoside analog libraries
US7144871B2 (en) 2002-02-19 2006-12-05 Cv Therapeutics, Inc. Partial and full agonists of A1 adenosine receptors
US20040043959A1 (en) * 2002-03-04 2004-03-04 Bloom Laura A. Combination therapies for treating methylthioadenosine phosphorylase deficient cells
KR100944140B1 (en) * 2002-03-20 2010-02-24 스미또모 가가꾸 가부시끼가이샤 Positive resist composition
AU2002951247A0 (en) 2002-09-06 2002-09-19 Alchemia Limited Compounds that interact with kinases
WO2005005450A1 (en) 2003-07-15 2005-01-20 Mitsui Chemicals, Inc. Method of synthesizing cyclic bisdinucleoside
AU2004311702A1 (en) 2003-12-19 2005-07-21 Koronis Pharmaceuticals, Inc. Mutagenic heterocycles
EP1844062A2 (en) 2005-01-21 2007-10-17 Methylgene, Inc. Inhibitors of dna methyltransferase
WO2008001101A2 (en) 2006-06-29 2008-01-03 Astex Therapeutics Limited Pharmaceutical combinations
US20080132525A1 (en) 2006-12-04 2008-06-05 Methylgene Inc. Inhibitors of DNA Methyltransferase
US8962580B2 (en) 2008-09-23 2015-02-24 Alnylam Pharmaceuticals, Inc. Chemical modifications of monomers and oligonucleotides with cycloaddition
SG181703A1 (en) 2009-12-18 2012-07-30 Harvard College Beta-cell replication promoting compounds and methods of their use
US9145438B2 (en) 2010-12-03 2015-09-29 Epizyme, Inc. 7-deazapurine modulators of histone methyltransferase, and methods of use thereof
US9029343B2 (en) 2010-12-03 2015-05-12 Epizyme, Inc. Modulators of histone methyltransferase, and methods of use thereof
EP2651885A1 (en) 2010-12-16 2013-10-23 Abbvie Inc. Anti-viral compounds
EP2694524B1 (en) 2011-04-04 2016-05-18 The U.S.A. As Represented By The Secretary, Department Of Health And Human Services 2'-o-aminooxymethyl nucleoside derivatives for use in the synthesis and modification of nucleosides, nucleotides and oligonucleotides
JP2014530910A (en) 2011-10-24 2014-11-20 グラクソスミスクライン、インテレクチュアル、プロパティー、ナンバー２、リミテッドＧｌａｘｏｓｍｉｔｈｋｌｉｎｅ Ｉｎｔｅｌｌｅｃｔｕａｌ Ｐｒｏｐｅｒｔｙ Ｎｏ．２ Ｌｉｍｉｔｅｄ New compounds
WO2013151975A1 (en) 2012-04-02 2013-10-10 Northeastern University Compositions and methods for the inhibition of methyltransferases
WO2014035140A2 (en) 2012-08-30 2014-03-06 Kainos Medicine, Inc. Compounds and compositions for modulating histone methyltransferase activity
US20140100184A1 (en) 2012-08-31 2014-04-10 Baylor College Of Medicine Selective inhibitors of histone methyltransferase dot1l
JP2016505000A (en) * 2012-12-21 2016-02-18 エピザイム，インコーポレイティド PRMT5 inhibitors and uses thereof
WO2014100716A1 (en) 2012-12-21 2014-06-26 Epizyme, Inc. Prmt5 inhibitors and uses thereof
JP2016505002A (en) 2012-12-21 2016-02-18 エピザイム，インコーポレイティド PRMT5 inhibitors containing dihydroisoquinoline or tetrahydroisoquinoline and uses thereof
US9604930B2 (en) * 2012-12-21 2017-03-28 Epizyme, Inc. Tetrahydro- and dihydro-isoquinoline PRMT5 inhibitors and uses thereof
EP2975938A4 (en) 2013-03-15 2017-02-15 Ohio State Innovation Foundation Inhibitors of prmt5 and methods of their use
CA2935944A1 (en) 2014-01-09 2015-07-16 The J. David Gladstone Institutes, A Testamentary Trust Established Under The Will Of J. David Gladstone Substituted benzoxazine and related compounds
EP3160477A4 (en) 2014-06-25 2018-07-04 Epizyme, Inc. Prmt5 inhibitors and uses thereof
NZ728162A (en) 2014-07-01 2023-06-30 Takeda Pharmaceuticals Co Heteroaryl compounds useful as inhibitors of sumo activating enzyme
CN107278205A (en) 2015-02-24 2017-10-20 辉瑞大药厂 Substituted nucleoside derivatives useful as anticancer agents
TWI730980B (en) 2015-08-26 2021-06-21 比利時商健生藥品公司 Novel 6-6 bicyclic aromatic ring substituted nucleoside analogues for use as prmt5 inhibitors
AU2017230658B2 (en) 2016-03-10 2021-03-04 Janssen Pharmaceutica Nv Substituted nucleoside analogues for use as PRMT5 inhibitors
AU2017338269B2 (en) * 2016-10-03 2021-03-25 Janssen Pharmaceutica Nv Novel monocyclic and bicyclic ring system substituted carbanucleoside analogues for use as PRMT5 inhibitors
WO2018065365A1 (en) 2016-10-03 2018-04-12 Janssen Pharmaceutica Nv Novel monocyclic and bicyclic ring system substituted carbanucleoside analogues for use as prmt5 inhibitors
WO2018154104A1 (en) 2017-02-27 2018-08-30 Janssen Pharmaceutica Nv Use of biomarkers in identifying cancer patients that will be responsive to treatment with a prmt5 inhibitor
BR112020010815A2 (en) 2017-12-08 2020-11-10 Janssen Pharmaceutica Nv spirobicyclic analogs

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